Systems and methods for ex-vivo organ care and for using lactate as an indication of donor organ status

ABSTRACT

The invention provides, in various embodiments, systems, devices and methods relating to ex-vivo organ care. In certain embodiments, the invention relates to maintaining an organ ex-vivo at near-physiologic conditions. The present application describes a method for using lactate measurement in the arterial and the venous blood lines of the Organ Care System Heart perfusion device to evaluate the:  1 ) The overall perfusion status of an isolated heart and  2 ) The metabolic status of an isolated heart and  3 ) the overall vascular patency of an isolated donor heart. This aspect of the present invention uses the property of myocardial cell&#39;s unique ability to produce/generate lactate when they are starved for oxygen and metabolize/utilize lactate for energy production when they are well perfused with oxygen.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/396,296, filed on Apr. 26, 2019, now U.S. Pat. No. 10,736,314, issuedAug. 11, 2020, entitled “Systems and Methods for Ex-Vivo Organ Care andFor Using Lactate as an Indication of Donor Organ Status”; which is acontinuation of U.S. patent application Ser. No. 15/857,953, filed Dec.29, 2017, now U.S. Pat. No. 10,321,676, issued on Jun. 18, 2019,entitled “System and Methods for Ex-Vivo Organ Care and for UsingLactate as an Indication of Donor Organ Status”; which is a continuationof U.S. patent application Ser. No. 13/587,810, filed Aug. 16, 2012, nowU.S. Pat. No. 9,894,894, issued Feb. 20, 2018, entitled “Systems andMethods for Ex-Vivo Organ Care and for Using Lactate as an Indication ofDonor Organ Status”; which is a divisional of U.S. application Ser. No.11/790,405, filed on Apr. 25, 2007, now U.S. Pat. No. 8,304,181, issuedNov. 6, 2012, entitled “Method for Ex-Vivo Organ Care and For UsingLactate as an Indication of Donor Organ Status”; which is acontinuation-in-part of U.S. patent application Ser. No. 11/246,902,filed on Oct. 7, 2005, now U.S. Pat. No. 8,465,970, issued Jun. 18,2013, entitled “Systems and Methods for Ex-Vivo Organ Care”; whichclaims the benefit of U.S. Provisional Patent Application Ser. No.60/616,835, filed on Oct. 7, 2004; U.S. Provisional Patent ApplicationSer. No. 60/694,971, filed on Jun. 28, 2005; and U.S. Provisional PatentApplication Ser. No. 60/725,168, filed on Oct. 6, 2005. Thespecifications of each of the foregoing are incorporated by referenceherein in their entireties.

FIELD OF THE INVENTION

The invention generally relates to systems, methods, and devices forex-vivo organ care. In various embodiments, the invention relates tocaring an organ ex-vivo at physiologic or near-physiologic conditionsand methods to indicate adequate perfusion and oxygen delivery to themyocardial cells.

BACKGROUND OF THE INVENTION

Current organ preservation techniques typically involve hypothermicstorage of the organ in a chemical perfusate solution on ice. In thecase of a heart, it is typically arrested, and cooled with thestorage/cardioplegic solution in a hypothermic, non-functioning state.These techniques utilize a variety of cardioplegic solutions, none ofwhich sufficiently protect the heart from myocardial damage resultingfrom ischemia. Such injuries are particularly undesirable when an organ,such as a heart, is intended to be transplanted from a donor into arecipient. In addition to myocardial damage resulting from ischemia,reperfusion of a heart may exacerbate the myocardial injury and maycause coronary vascular endothelial and smooth muscle injury, which maylead to coronary vasomotor dysfunction.

Using conventional approaches, such injuries increase as a function ofthe length of time an organ is maintained ex-vivo. For example, in thecase of a heart, typically it may be maintained ex-vivo for only a fewhours before it becomes unusable for transplantation. This relativelybrief time period limits the number of recipients who can be reachedfrom a given donor site, thereby restricting the recipient pool for aharvested heart. Even within the few hour time limit, the heart maynevertheless be significantly damaged. A significant issue is that theremay not be any apparent indication of the damage. Because of this,less-than-optimal organs may be transplanted, resulting inpost-transplant organ dysfunction or other injuries. Thus, it would bedesirable to develop techniques that can extend the time during which anorgan can be preserved in a healthy state ex-vivo. Such techniques wouldreduce the risk of transplantation failure and enlarge potential donorand recipient pools.

Effective preservation of an ex-vivo organ would also provide numerousother benefits. For instance, prolonged ex-vivo preservation wouldpermit more careful monitoring and functional testing of the harvestedorgan. This would in turn allow earlier detection and potential repairof defects in the harvested organ, further reducing the likelihood oftransplantation failure. The ability to perform simple repairs on theorgan would also allow many organs with minor defects to be saved,whereas current transplantation techniques require them to be discarded.

In addition, more effective matching between the organ and a particularrecipient may be achieved, further reducing the likelihood of eventualorgan rejection. Current transplantation techniques rely mainly onmatching donor and recipient blood types, which by itself is arelatively unreliable indicator of whether or not the organ will berejected by the recipient. A more preferred test for organ compatibilityis a Human Leukocyte Antigen (HLA) matching test, but current coldischemic organ preservation approaches preclude the use of this test,which can often require 12 hours or more to complete.

Prolonged and reliable ex-vivo organ care would also provide benefitsoutside the context of organ transplantation. For example, a patient'sbody, as a whole, can typically tolerate much lower levels of chemo-,bio- and radiation therapy than many particular organs. An ex-vivo organcare system would permit an organ to be removed from the body andtreated in isolation, reducing the risk of damage to other parts of thebody.

There exists a need for a sensitive indicator for determining the statusof a donor organ, especially the perfusion status. Lactate, also calledlactic acid, is a byproduct/end product of anaerobic metabolism inliving cells/tissues/organs. Lactate is generated when there is no orlow oxygen in the cell to metabolize glucose for basic energy productionthrough the glycolysis pathway. Many clinical and scientific manuscriptshave described the measurement of total lactate as an indication of bodystress, trauma, injury or some form of hypo-perfusion state.

In view of the foregoing, improved systems, methods, and devices forcaring for and evaluating the perfusion status of an organ ex-vivo areneeded.

SUMMARY OF THE INVENTION

The invention addresses the deficiencies in the prior art by, in variousembodiments, providing improved systems, methods and devices relating toportable ex-vivo organ care. More particularly, according to variousaspects, the invention provides systems, methods and devices relating toportable ex-vivo heart care. According to one advancement, the heartcare system of the invention maintains the heart in a beating state at,or near, normal physiological conditions. To this end, the systemcirculates an oxygenated, nutrient enriched perfusion fluid to the heartat or near physiological temperature, pressure and flow rate. Accordingto one implementation, the system employs a blood product-basedperfusion fluid to more accurately mimic normal physiologic conditions.In alternative embodiments, the system uses a synthetic blood substitutesolution, while in other embodiments, the solution may contain a bloodproduct in combination with a blood substitute product.

The present application describes a method for using lactate measurementin the arterial and the venous blood lines of the Organ Care SystemHeart perfusion device to evaluate the: 1) The overall perfusion statusof an isolated heart and 2) The metabolic status of an isolated heartand 3) the overall vascular patency of an isolated donor heart. Thisaspect of the present invention is based on the ability of myocardialcells to produce/generate lactate when they are starved for oxygen andmetabolize/utilize lactate for energy production when they are wellperfused with oxygen.

A system for evaluating the perfusion status of a heart is disclosed. Inparticular, an organ care system according to an aspect of the presentinvention includes a module that has a chassis, an organ chamberassembly that is mounted to the chassis and is adapted to contain aheart during perfusion. The organ care system includes a fluid conduitwith a first interface for connecting to an aorta of the heart and asecond interface for connecting to a pulmonary vein of the heart. Theorgan care system includes a Lactate A sensor for sensing lactate in thefluid conduit connected to the aorta of the heart, a Lactate V sensorfor sensing lactate in the fluid conduit connected to the pulmonary veinof the heart, wherein a Lactate V-A differential is calculated usingvalues sensed by the Lactate A sensor and the Lactate V sensor. Theorgan care system may also include a sensor for measuring the aorticpressure in the OCS.

A method of determining heart perfusion status is also disclosed. Inparticular, one aspect of the present invention includes a method forevaluating heart perfusion status includes the steps of placing a heartin a protective chamber of an organ care system, pumping a perfusionfluid into the heart, providing a flow of the perfusion fluid away fromthe heart, measuring the lactate value of the fluid leading to theheart, measuring the lactate value of the fluid leading away from theheart, and evaluating the status of the heart using the measured lactatevalues. Additionally, the method can include the step of subtracting thelactate value of the fluid leading to the heart from the lactate valueof the fluid leading away from the heart to determine a V-A lactatedifferential.

According to another advancement, the system of the invention canmaintain a harvested heart in two modes of operation; a normal aorticflow mode (also referred to as “normal flow mode”), and a retrogradeaortic flow mode (also referred to as a “retrograde flow mode”).Generally, in the normal flow mode, the system circulates the perfusionfluid to the heart in the same manner as blood would circulate in thehuman body. More particularly, the perfusion fluid enters the heart viathe left atrium and is flowed away from the heart via the right and leftventricles. In normal flow mode, the system pumps the perfusion fluid tothe heart at a rate of between about 1 liter/min and about 5liters/minute. This mode is useful, for example, for performingfunctional testing to verify that the heart is defect free, both priorand subsequent to transportation to a donor location. Alternatively, inretrograde flow mode, the system flows the perfusion fluid into theheart via the aorta, through the coronary sinus, and then out of theheart via the right ventricle. In this mode of operation, the systemreduces the flow rate of the perfusion fluid to between about 300milliliters/min and about 1 liter/min. The inventors have found that theretrograde flow path, along with the reduced flow rate, reduces damageto the heart during extended periods of ex-vivo care. Thus, according toone feature of the invention, the heart is transported to a donor sitein retrograde flow mode.

According to various aspects, the systems and/or devices of theinvention include, and/or the methods of the invention employ, one ormore of: an organ chamber assembly for containing a heart during ex-vivocare; a reservoir for containing and optionally, defoaming and/orfiltering a volume of perfusion fluid; a perfusion fluid pump forpumping/circulating perfusion fluid to and from the harvested heart; aheater assembly for maintaining the temperature of the perfusion fluidat or near physiological temperatures; a flow mode selector valve forswitching between normal and retrograde flow modes; an oxygenator forre-oxygenating the perfusion fluid subsequent to it being expelled bythe heart; a nutritional subsystem for replenishing nutrients in theperfusion fluid as they are metabolized by the heart and for providingpreservatives to the perfusion fluid to reduce, for example, ischemiaand/or other reperfusion related injuries to the heart; a sensorsubsystem for monitoring, for example, temperature, pressure, flow rateand/or oxygenation of the perfusion fluid, and/or electrical signalsfrom the heart and/or the various components employed to maintainsuitable flow conditions to and from the heart; an operator interfacefor assisting an operator in monitoring system operation and/or thecondition of the heart, and/or for enabling the operator to set variousoperating parameters; a power subsystem for providing fault tolerantpower to the organ care system; and a control subsystem for controllingoperation of the organ care system.

Operationally, in one practice, a heart is harvested from a donor andaffixed to the organ chamber assembly by a process of cannulation. Theperfusion fluid pump pumps perfusion fluid from a reservoir to theheater assembly. The heater assembly heats the perfusion fluid to ornear a normal physiological temperature. According to one embodiment,the heater assembly heats the perfusion fluid to between about32.degree. C. and about 37.degree. C. From the heater assembly, theperfusion fluid flows to the flow mode selector valve. Initially, theflow mode selector valve is positioned for retrograde flow mode todirect the perfusion fluid from the heater assembly to a first interfaceon the organ chamber assembly. Also referred to as an aorta interface orthe left ventricle interface, the first interface is cannulated tovascular tissue of the left ventricle (e.g., an aorta stub) via aconduit located within the organ chamber assembly. The heart then pumpsthe perfusion fluid out of the heart through the right ventricle via asecond interface on the organ chamber assembly. The second interface,also referred to as a pulmonary artery interface or right ventricleinterface, is cannulated to vascular tissue of the right ventricle(e.g., a pulmonary artery stub) via a conduit located within the organchamber assembly. In retrograde flow mode, fluid is not pumped into orout of the left side of the heart other than in the form of a smalltrickle of perfusion fluid, which is delivered to moisten the leftatrium. In response to the flow mode selector valve being in the normalflow mode position, it directs the perfusion fluid into the left atriumof the heart via a third interface on the organ chamber assembly. Thethird interface, also referred to as a pulmonary vein interface or leftatrium interface, is cannulated to the vascular tissue of the leftatrium (e.g., a pulmonary vein stub) via a conduit located within theorgan chamber assembly. The heart then expels the perfusion fluidthrough the left ventricle via the aorta interface, and through theright ventricle via the pulmonary artery interface.

In both modes of operation, from the pulmonary artery interface, theperfusion fluid flows into the oxygenator. The oxygenator receivesoxygen from an external or onboard gas source and applies gas (e.g.,oxygen) to the perfusion fluid prior to returning it to the reservoir.The system may include one or more oxygen saturation sensors to measurethe oxygen saturation level of the perfusion fluid to ensure that theperfusion fluid is maintained at physiological oxygen levels. In theembodiments where the perfusion fluid is blood-product based, itcontains red blood cells (i.e., oxygen carrying cells). Optionally, theoxygen sensors also provide a hematocrit measurement of theconcentration of red blood cells in the perfusion fluid.

In both normal and retrograde flow modes, the nutritional subsysteminfuses the perfusion fluid with a supply of maintenance solutions asthe perfusion fluid flows through the system, and in some embodiments,while it is in the reservoir. According to one feature, the maintenancesolutions include nutrients, such as glucose. According to anotherfeature, the maintenance solutions include a supply of therapeuticsand/or preservatives (e.g., cardio stimulants, insulin, amino acids,etc.) for reducing ischemia and/or other reperfusion related injuries tothe heart.

According to another practice, the perfusion fluid includes bloodremoved from the donor through a process of exsanguination duringharvesting of the heart. Initially, the blood from the donor is loadedinto the reservoir and the cannulation locations in the organ chamberassembly are bypassed with a bypass conduit to enable normal mode flowof perfusion fluid through the system without a heart being present.Prior to cannulating the harvested heart, the system may be primed bycirculating the exsanguinated donor blood through the system to heat,oxygenate and/or filter it. Nutrients, preservatives, and/or othertherapeutics may also be provided during priming via the infusion pumpof the nutritional subsystem. During priming, various parameters mayalso be initialized and calibrated via the operator interface duringpriming. Once primed and running appropriately, the pump flow is reducedor cycled off, the bypass conduit is removed from the organ chamberassembly, and the heart is cannulated into the organ chamber assembly.The pump flow is then restored or increased, as the case may be.According to one feature, the operator interface may be plugged into thesystem via a hard wired connection, or may be unplugged and used towirelessly communicate with the system of the invention.

According to one feature, the system includes a plurality of compliancechambers. The compliance chambers are essentially small inline fluidaccumulators with flexible, resilient walls for simulating the humanbody's vascular compliance by aiding the system in more accuratelymimicking blood flow in the human body, for example, by providing flowback-pressure and/or by filtering/reducing fluid pressure spikes due,for example, to flow rate changes. In one configuration, compliancechambers are located on either side of the flow mode selector valve andon the output of the perfusion fluid pump. According to one feature, acompliance chamber is located next to a clamp used for regulating backpressure seen by the aorta during normal flow mode operation.

According to one implementation, the sensor subsystem includes anelectrocardiogram (ECG) sensor for monitoring electrical signals fromthe heart. According to one embodiment, the control subsystemsynchronizes the pumping of the perfusion fluid to the heart with theECG signals. According to one feature, the ECG signals include anr-wave, and the control subsystem uses the r-wave to synchronize thefluid pumping with a diastolic state of the heart. According to anotherfeature, the control subsystem adjusts pump stroke volume and/or pumprate in dependence on the ECG signals. For example, in one embodiment,the control subsystem reduces the pump stroke volume as heart rateincreases in order to maintain blood flow. In another embodiment, thesystem reduces the pump stroke volume in response to detecting anirregular heart rate. In both cases, the result is to reduce fluidvolume pumped to the heart, which in turn reduces the likelihood ofcausing damage to the heart. In various embodiments, the sensors includeperfusion fluid flow rate and/or flow pressure sensors, which providefeedback for controlling the perfusion fluid pump. According to oneembodiment, to more accurately simulate normal circulation through thebody, the pump of the system is a pulsatile pump.

According to one aspect of the invention, the organ chamber assemblyincludes a plurality of improved features. More particularly, in oneconfiguration, the organ chamber assembly of the invention includes ahousing, an outer lid and an intermediate lid. The housing includes abottom and one or more walls for containing the organ. The intermediatelid covers an opening to the housing for substantially enclosing theorgan within the housing, and includes a frame and a flexible membranesuspended within the frame. The flexible membrane, preferably, istransparent but may be opaque, translucent, or substantiallytransparent. According to one feature, the flexible membrane includessufficient excess membrane material to contact an organ contained withinthe chamber. This feature enables a medical operator to touch/examinethe organ indirectly through the membrane while still maintainingsterility of the system and the organ. The outer lid opens and closesover the intermediate lid independently from the intermediate lid.Preferably, the outer lid is rigid enough to protect the organ fromphysical contact, indirect or direct.

According to one implementation, the intermediate lid is hinged to thehousing. The intermediate lid may also include a latch for securing theintermediate lid closed over the opening of the organ chamber. The outerlid may be similarly hinged and latched. In some configurations, gasketsare provided for forming a fluid seal between the intermediate lid frameand the one or more organ chamber walls, and/or for forming a fluid sealbetween the periphery of the outer lid and the frame of the intermediatelid.

Optionally, the organ chamber assembly includes a pad or a sac assemblysized and shaped for interfitting within a bottom of the housing.Preferably, the pad assembly includes a pad formed from a materialresilient enough to cushion the organ from mechanical vibrations andshocks during transport. In the case of the organ chamber assembly beingconfigured to receive a heart, according to one feature, the pad of theinvention includes a mechanism for receiving at least one electrode. Themechanism may include, without limitation, one or more slots,indentations, protrusions, through apertures, partially throughapertures, hooks, eyelets, snaps, adhesive patches, or the like.According to one advantage, the mechanism allows for adjustableplacement of the at least one electrode on or in the pad to accommodatedifferently sized and shaped hearts. According to one embodiment, thepad includes a through-aperture through which an electrical lead of theat least one electrode may pass.

According to one embodiment, the pad assembly includes at least oneelectrode adjustably positioned at a location on or in the pad in such away as to facilitate contact with a heart placed on the pad in the organchamber assembly. According to one configuration, the at least oneelectrode rests on the surface of the pad and is held in place by theweight of the heart. In another configuration, the at least oneelectrode is glued to the surface of the pad. The at least one electrodeincludes one or more sensors for monitoring one or more electricalsignals from the heart. It may also include one or more defibrillatorcontacts for providing an electrical signal to the heart. One advantageof the pad/electrode configuration of the invention is that it does notrequire the at least one electrode to be permanently or temporarilysutured or otherwise mechanically connected to the heart. Instead,electrical connection is made by placing the heart on the one or moreelectrodes. In one configuration, the at least one electrode includes anintegrated sensor and defibrillation contact that allows the user tomonitor electrical signals from the heart and provide an electricalsignal to the heart through a common electrical interface connection tothe organ chamber assembly. According to another feature, the commonelectrical interface includes one or more electrical ports on the organchamber assembly for transferring electrical signals between the atleast one electrode within the chamber and instrumentation locatedexternal to the housing. By way of example, the ports may provide theECG signals to an external processor and/or display, and/or may providedefibrillation power to the electrodes.

Optionally, the organ chamber housing also includes a base for anglingthe housing for optimal heart function. According to one feature, thebase maintains a heart contained within the organ chamber at an angle ofbetween about 30.degree. and about 60.degree. relative to horizontal.

According to another aspect, the perfusion fluid heater assembly of theinvention includes a plurality of improved features relating toproviding a compact, solid state mechanism for heating the perfusionfluid. Some features of the heater assembly make it particularlysuitable for heating blood-product based embodiments of the perfusionfluid. In one embodiment, the heater assembly of the invention includesan inlet, an outlet, a flow channel, first and second flow channelplates and a first heater. The flow channel is formed between the firstand second flow channel plates. The inlet flows the perfusion fluid intothe flow channel and the outlet flows the perfusion fluid out of theheater. The first and second flow channel plates have substantiallybioinert perfusion fluid contacting surfaces for providing directcontact with the perfusion fluid flowing through the channel. Theperfusion fluid contacting surfaces may be formed, for example, from atreatment or coating on a substrate or may be the substrate surfaceitself. The first heater is thermally coupled to the first flow channelplate for heating the first flow channel plate. In one configuration,the first heater is located on a nonperfusion fluid contacting side ofthe first flow channel plate. According to a further embodiment, theheater assembly of the invention also includes a second heater thermallycoupled to the second flow channel plate for heating the second flowchannel plate to provide a more uniform temperature distribution in theflow channel.

According to one configuration, the heater assembly includes a firstheater plate disposed between the first heater and the first flowchannel plate for thermally coupling heat from the first heater to thefirst flow channel plate. According to one feature, the first heaterplate is formed from a material, such as aluminum, that conducts anddistributes heat from the heater relatively uniformly. The uniformlydistributed heat of the heater plate is then coupled to the firstchannel plate, which preferably is formed from a bioinert material, suchas titanium, which does not necessarily provide sufficiently uniformheat distribution if put in direct contact with the heater. The heaterassembly may also include a second heater plate disposed between thesecond heater and the second flow channel plate for coupling heat fromthe second heater to the second flow channel plate.

According to one embodiment, the first and/or second heaters of theinvention are resistive heaters. In one configuration, they each includea resistive heating element formed on a polyimide substrate. Accordingto a further configuration, the resistive heating elements have aresistance of about 5 ohms. In other configurations, the resistance ofthe heating elements ranges from about 3 ohms to about 10 ohms.

Optionally, the heater assembly of the invention includes one or moretemperature sensors. For example, the heater assembly may include atemperature sensor at its outlet for reporting the temperature of theperfusion fluid exiting the heater to the control subsystem. The signalfrom this sensor may be employed in a feedback loop to control drivesignals to the first and second heaters to control the temperature ofthe heater plates. Additionally, to ensure that the perfusion fluidcontacting surfaces of the heater plates do not reach a temperature thatmight damage the perfusion fluid, the heater assembly may also includetemperature sensors for reporting the temperature of the first and/orsecond heaters to the control subsystem. The signals from these sensorsmay also be employed in a feedback loop to further control the drivesignals to the first and/or second heaters to limit the maximumtemperature of the heater plates. According to a variation of thisembodiment, the heater assembly may include temperature sensors forreporting the temperature of the first and/or second heaters to thecontrol subsystem.

To provide improved contact between the first and/or second heaters andtheir respective heater plates, and also between the first and/or secondheater plates and their respective flow channel plates, the heaterassembly may also include first and second resilient pads disposed onthe respective heaters for maintaining the first heater in contact withthe first heater plate and the second heater in contact with the secondheater plate in response to compressive force. The compressive force maybe provided, for example, by way of one or more heater assembly housingcomponents. According to one feature, the heater assembly includeshousing components formed from a polycarbonate, and weighs less thanabout 5 lb, while in other embodiments the heater assembly may weighless than about 4 lb, less than about 3 lb, less than about 2 lb, oreven less than about 1 lb. According to another feature, the heaterassembly is about 6.75 inches long, about 2.75 inches wide, and about2.5 inches thick, all exclusive of inlet and outlet ports andtemperature sensor assemblies. According to another feature, the heaterassembly is a single use disposable assembly.

According to one embodiment, in operation, the heater assembly usesbetween about 1 Watt and about 200 Watts of power. According to afurther embodiment, the heater assembly of the invention is sized andshaped to transition about 2.5 liters of perfusion fluid flowing throughthe channel at a rate of between about 300 ml/min and about 5 L/min froma temperature of less than about 30.degree. C. to a temperature of about37.degree. C. in less than about 25 minutes, less than about 20 minutes,less than about 15 minutes or even less than about 10 minutes, withoutcausing substantial hemolysis to the blood cells or denaturation of anyproteins that may be contained in the perfusion fluid.

According to a further embodiment, the power subsystem of the inventionprovides a fault tolerant battery arrangement. More particularly, aplurality of batteries are interlocked such that all of them may not beremoved from the system at any particular time while the system isoperating to maintain an organ. According to one feature, the powersubsystem can switch between external power and onboard battery backup,without interruption of system operation. According to another feature,the power subsystem automatically allocates externally supplied powerbetween powering the system, charging the batteries, and charginginternal batteries of the wireless operator interface.

According to another aspect, the invention segments various subsystemsand components of the portable organ care system into two modules; aportable multiple use module and a single use disposable module.According to one segmentation, the system of the invention generallyassigns perfusion fluid contacting (and thus, blood product contactingin embodiments employing a blood product perfusion fluid) components tothe disposable module, and non perfusion-fluid-contacting (and thus,non-blood product contacting components) to the multiple use module.However, the disposable unit may also include non-blood contactingcomponents. According to one feature, the perfusion-fluid contactingcomponents may be coated or bonded with heparin or other anticoagulantor biocompatible material to reduce the inflammatory response that mayotherwise arise when the perfusion fluid contacts the surfaces of thecomponents. Heparin may also be added to the maintenance solutions forcirculation within the system.

In one embodiment, the portable multiple use module includes a portablehousing constructed on a portable chassis, and the single use disposablemodule includes a disposable chassis. To reduce weight, in oneconfiguration, the single use module chassis is formed from moldedplastic such as polycarbonate, and the multiple use module chassis isformed from molded materials such as polycarbonate or carbon fibercomposites. According to one feature, the single use chassis unloadedwith components weighs less than about 12 pounds and the loaded singleuse module weighs less than about 18 pounds. According to anotherfeature, the multiple use housing and chassis unloaded with componentsweighs less than about 50 pounds, and when loaded with a multiple usemodule, batteries, gas, maintenance solutions, perfusion fluid and aheart, weighs about 85 pounds or less. According to another advantage,the system of the invention including both single and multiple usemodules, exclusive of any perfusion, nutrient, preservative or otherfluids, batteries and oxygen supply, weighs less than about 65 pounds.

The single use disposable chassis is sized and shaped for interlockingwith the portable chassis of the multiple use module for electrical,mechanical, gas and fluid interoperation with the multiple use module.According to one feature, the multiple and single use modulescommunicate with each other via an optical interface, which comes intooptical alignment automatically upon the single use disposable modulebeing installed into the portable multiple use module. According toanother feature, the portable multiple use module provides power to thesingle use disposable module via spring loaded connections, which alsoautomatically connect upon the single use disposable module beinginstalled into the portable multiple use module. According to onefeature, the optical interface and spring loaded connections ensure thatconnection between the single and multiple modules is not lost due tojostling, for example, during transport over rough terrain.

In various embodiments, the organ chamber assembly and the pumpinterface assembly both mount to the disposable chassis. The pumpinterface assembly is aligned to receive a pumping force from the pumpdriver of the perfusion fluid pump, and the interface assembly thentranslates the pumping force to the perfusion fluid to circulate theperfusion fluid to the organ chamber assembly. According to oneembodiment, the perfusion fluid pump is a pulsatile pump and the pumpinterface assembly includes a housing, a first deformable membrane, afluid inlet, and a fluid outlet. The housing of the pump interfaceassembly includes an interior side and an exterior side. The firstdeformable membrane mounts in fluid tight interconnection with theinterior side of the housing to form a chamber between an interior sideof the first deformable membrane and the interior side of the housing.The fluid inlet receives perfusion fluid, for example, from thereservoir, and provides the fluid into the chamber in response to thepump driver moving in a direction away from the interior side of thehousing, and thus deforming the first deformable membrane in the samedirection. The outlet expels the perfusion fluid out of the chamber, forexample, to the heater assembly, in response to the pump driver movingin a direction toward the interior side of the housing.

According to one configuration, the pump interface assembly includes abracket for fitting over a periphery of the first deformable membrane toform the fluid tight seal between the periphery of the interior side ofthe deformable membrane and a periphery of the interior side of thehousing. According to a further configuration, the pump interfaceassembly includes a gasket for providing a fluid tight seal between theperfusion fluid pump driver and the pump interface housing.

According to one implementation, the system also includes a flow valvepositioned on the input to the fluid inlet. The flow valve includes aball valve assembly oriented to open and pass the perfusion fluid intothe chamber through the bidirectional fluid inlet in response to thepump driver moving in the direction away from the interior side of thehousing, and oriented to close and stop perfusion fluid passing back outof the chamber through the fluid inlet in response to the pump drivermoving in the direction toward the interior surface of the housing. In afurther implementation, the fluid outlet also includes a ball valveassembly oriented to close in response to the pump driver moving in thedirection away from the interior surface of the housing, and to open toexpel the organ perfusion fluid through the fluid outlet in response tothe pump driver moving in the direction toward the interior side of thehousing.

Optionally, the perfusion fluid pump rigidly mounts to the portablemultiple use chassis, the pump interface assembly rigidly mounts to thedisposable single use chassis, and the system includes features forautomatically forming a fluid tight seal between the perfusion pumpdriver and the pump interface assembly in response to the single usedisposable module being interfitted with the portable multiple usemodule. More particularly, the pump interface assembly may include oneor more projections out of the exterior side of the interface assemblyhousing, sized and shaped for engaging with and abutting one or moresurfaces on the portable multiple-use module to force/draw the interiorside of the pump interface assembly housing in a direction toward thepump driver of the perfusion pump.

According to one feature, the pump interface assembly includes a seconddeformable membrane mounted adjacent to the first deformable membranefor providing a fault tolerant seal in case the first deformablemembrane tears. According to another feature, the pump interfaceassembly is formed at least in part from a polycarbonate or other moldedplastic material, to reduce the weight of the single use disposablemodule.

In one embodiment, the perfusion fluid reservoir mounts to the singleuse disposable chassis and is in fluid communication with the organchamber. According to a further embodiment, the flow mode selector valvemounts to the disposable chassis. In other embodiments, the solid stateperfusion heater of the invention mounts to the disposable chassis. Theoxygenator is preferably provided with the multiple-use module, but incertain embodiments may alternatively be part of the disposable module.The oxygen source feeding the oxygenator may be included on the multipleuse portable chassis, may be part of the multiple-use module, or may beexternal to the system.

In one configuration, the various sensors associated with the heaterassembly, the oxygenator and/or the perfusion fluid pump are included onthe disposable single use module. However, this need not be the case,for example, with regard to non-perfusion fluid contacting sensors.According to one embodiment, the single use disposable module employs anoxygen, sensor including in-line cuvette through which the perfusionfluid passes, an optical source for directing light at the perfusionfluid passing through the cuvette, and an optical sensor for measuringan optical quality of the perfusion fluid passing through the cuvette.Preferably, the in-line cuvette seamlessly or substantially seamlesslyattaches to a perfusion fluid flow conduit to reduce turbulence in theperfusion fluid and provide one or more accurate measurements. Theseamless or substantially seamless configuration also reduces damage toany blood based components of the perfusion fluid.

According to a further configuration, the disposable single-use moduleincludes the above-mentioned plurality of inline compliance chamberslocated, for example, at the outlet of the perfusion fluid pump, and oneither side of the mode select valve between the organ chamber and themode select valve. In a further embodiment, the disposable single-usemodule includes a plurality of ports for sampling fluids from the organchamber assembly. According to one feature, the ports are interlockedsuch that sampling fluid from a first of the plurality of portsprohibits simultaneously sampling fluids from a second port of theplurality. This safety feature reduces the likelihood of mixing fluidsamples and inadvertently opening the ports. In one embodiment, theorgan chamber assembly includes ports for fluid interconnection with oneor more of the pulmonary artery, aorta, and left atrium interfaces.

In another aspect, the invention is directed to a method of preserving aheart ex-vivo. The method includes placing a heart in a protectivechamber of a portable organ care system, pumping a perfusion fluid tothe heart, the perfusion fluid being at a temperature of between about25.degree. C. and about 37.degree. C., and at a volume of between about200 ml/min and about 5 L/min, monitoring one or more physiologiccharacteristics of the heart while it is beating in the protectivechamber, and adjusting a pumping characteristic based at least in parton the electrical characteristics to preserve the heart ex vivo.

According to another aspect, the invention is directed to a method ofpreserving a heart ex vivo, the method including the steps of placing aheart on one or more electrodes in a protective chamber of a portableorgan care system, pumping a perfusion fluid to the heart, the perfusionfluid being at a temperature of between about 25.degree. C. and about37.degree. C., and at a volume of between about 200 ml/min and about 5L/min, and monitoring electrical signals from the electrodes whilepumping the perfusion fluid to the heart to preserve the heart ex vivo.

In a further aspect, the invention is directed to a method oftransporting a heart ex vivo, including the steps of placing a heart fortransplantation in a protective chamber of a portable organ care system,pumping a perfusion fluid into the heart via an aorta of the heart,providing a flow of the perfusion fluid away from the heart via a rightventricle of the heart, and transporting the heart in the portable organcare system from a donor site to a recipient site while pumping theperfusion fluid into the heart via the aorta and providing the flow ofthe perfusion fluid away from the heart via the right ventricle.

According to an additional aspect, the invention is directed to a methodof evaluating a heart for transplantation, including the steps ofplacing a heart in a protective chamber of a portable organ care system,pumping a perfusion fluid into the heart via a left ventricle of theheart, providing a flow of the perfusion fluid away from the heart via aright ventricle of the heart, transporting the heart via the portableorgan care system from a donor site to a recipient site while pumpingthe perfusion fluid into the heart via the left ventricle and providingthe flow of the perfusion fluid away from the heart via the rightventricle; prior to transplanting the heart into a recipient, operatinga flow control external to the protective chamber to alter a flow of theperfusion fluid such that the perfusion fluid is pumped into the heartvia a left atrium of the heart and is flowed away from the heart via theright ventricle and the left ventricle of the heart; and performing anevaluation of the heart. In certain embodiments the evaluation includesperforming an HLA test on the heart while the perfusion fluid ispumping.

In another aspect, the invention is directed to a method of providingtherapy to a heart. The method includes placing a heart in a protectivechamber of a portable organ care system, pumping a perfusion fluid intothe heart via a left ventricle of the heart, providing a flow of theperfusion fluid away from the heart via a right ventricle of the heart,operating a flow control external to the protective chamber to alter aflow of the perfusion fluid such that the perfusion fluid is pumped intothe heart via a left atrium of the heart and is flowed away from theheart via the right ventricle and the left ventricle of the heart, andadministering a therapeutic treatment to the heart. The treatments mayinclude, for example, administering one or more of immunosuppressivetreatment, chemotherapy, gene therapy and irradiation therapy to theheart.

According to another aspect, the invention is directed to a method oftransplanting a heart. The method includes arresting a heart of a donor,explanting the heart from the donor, transferring the heart to an organcare system, and pumping a perfusion fluid to the heart in less than 30minutes after explanting the heart from the donor (so as to reduce theheart's explantation cold ischemia time), the perfusion fluid being at atemperature of between about 32.degree. C. and about 37.degree. C. Incertain embodiments the heart is brought to a temperature of betweenabout 35.degree. C. and about 37.degree. C. in less than 10 minutesafter transferring the heart to the organ care system.

These and other features and advantages of the invention are describedin further detail below with regard to illustrative embodiments of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures depict illustrative embodiments of the inventionin which like reference numerals refer to like elements. These depictedembodiments may not be drawn to scale and are to be understood asillustrative of the invention and not as limiting, the scope of theinvention instead being defined by the appended claims.

FIG. 1 is a schematic diagram of a portable organ care system accordingto an illustrative embodiment of the invention.

FIG. 2 is a diagram depicting a harvested heart.

FIG. 3 is a conceptual diagram depicting the harvested heart of FIG. 2interconnected with the organ care system of FIG. 1 in a normal flowmode configuration according to an illustrative embodiment of theinvention.

FIG. 4 is a conceptual diagram depicting the harvested heart of FIG. 2interconnected with the organ care system of FIG. 1 in a retrograde flowmode configuration according to an illustrative embodiment of theinvention.

FIGS. 5A-5F show various views of an organ chamber assembly of the typeemployed in the organ care system of FIG. 1 according to an illustrativeembodiment of the invention.

FIGS. 6A-6F show various views of a perfusion heater assembly of thetype employed in the organ care system of FIG. 1 according to anillustrative embodiment of the invention.

FIG. 7 shows a more detailed view of an exemplary resistive heaterelement of the type employed in the heater assembly of FIGS. 6A-6F.

FIGS. 8A-8C show various views of a perfusion fluid pump interfaceassembly according to an illustrative embodiment of the invention.

FIG. 9 shows a perspective view of a pump driver side of a perfusionfluid pump assembly of the type depicted in FIG. 1 , along with abracket for mounting with the perfusion pump interface assembly.

FIG. 10 shows a side view of the perfusion fluid pump interface assemblyof FIGS. 8A-8C mated with the pump driver side of the perfusion fluidpump assembly of FIG. 9 .

FIG. 11 depicts a block diagram of an illustrative control scheme forcontrolling operation of the organ care system of FIG. 1 .

FIG. 12 is a block diagram of an exemplary data acquisition subsystem ofthe type that may be employed with an the illustrative organ care systemof FIG. 1 .

FIG. 13 is a block diagram of an exemplary heating control subsystem ofthe type that may be employed for maintaining perfusion fluidtemperature in the illustrative organ care system of FIG. 1 .

FIG. 14 is a block diagram of an exemplary power management subsystem ofthe type that may be employed in the illustrative organ care system ofFIG. 1 .

FIG. 15 is a block diagram of an exemplary pumping control subsystem ofthe type that may be employed for controlling operation of a perfusionfluid pump assembly in the illustrative organ care system of FIG. 1 .

FIG. 16 is a graph depicting an r-wave with which the pumping controlsubsystem of FIG. 15 synchronizes according to an illustrativeembodiment of the invention.

FIG. 17A-17J depict exemplary display screens of the type that may beemployed with an operator interface according to an illustrativeembodiment of the invention.

FIGS. 18A and 18B show an exemplary implementation of the system of FIG.1 according to an illustrative embodiment of the invention.

FIGS. 19A-19C show various views of the system of FIGS. 18A and 18B withits top off and front panel open according to an illustrative embodimentof the invention.

FIG. 20A is a front perspective view of the system of FIGS. 18A and 18Bwith the top removed, the front panel open and the single use disposablemodule removed according to an illustrative embodiment of the invention.

FIG. 20B is a side view of a slot formed in a basin of the multiple usemodule of FIG. 20A for engaging with a corresponding projection in thesingle use disposable module.

FIG. 21A shows a mounting bracket for receiving and locking into placethe single use disposable module within the multiple use module of FIG.20A.

FIGS. 21B and 21C show installation of the single use disposable moduleinto the multiple use module using the mounting bracket of FIG. 21Aaccording to an illustrative embodiment of the invention.

FIGS. 22A-22C show exemplary mechanisms for automatically makingelectro-optical interconnections between the single use disposablemodule and the multiple use module during the installation of FIGS. 21Band 21C.

FIGS. 23A-23C show various views of the system of FIGS. 18A and 18B withall of the external walls removed according to an illustrativeembodiment of the invention.

FIG. 23D is a conceptual diagram showing interconnections between thecircuit boards of FIGS. 23A-23C according to an illustrative embodimentof the invention.

FIGS. 24A-24E show various top perspective views of a single usedisposable module according to an illustrative embodiment of theinvention.

FIGS. 25A-25C show various bottom perspective views of the illustrativesingle use disposable module of FIGS. 24A-24D.

FIGS. 26A and 26B depict the operation of a flow mode selector valveaccording to an illustrative embodiment of the invention.

FIGS. 27A and 27B show various top views of the single use disposablemodule of FIGS. 19A-19C with the top off of illustrative organ chamber.

FIGS. 28A-28C show various views of an exemplary hematocrit and oxygensaturation sensor of the type employed in the illustrative single usedisposable module of FIGS. 19A-19C.

FIG. 29A is a flow diagram depicting a donor-side process for removingan organ from a donor and placing it into the organ care system of FIG.1 according to an illustrative embodiment of the invention.

FIG. 29B is a diagram depicting a harvested heart with suture andcannulation sites according to an illustrative embodiment of theinvention.

FIG. 30 is a flow diagram depicting a recipient-side process forremoving an organ from the organ care system of FIG. 1 and transplantingit into a recipient according to an illustrative embodiment of theinvention.

FIG. 31 depicts a chart demonstrating electrolyte stability for an organunder going perfusion in forward mode according to an embodiment of theinvention.

FIG. 32 depicts a chart demonstrating electrolyte stability for an organunder going perfusion in retrograde mode according to another anembodiment of the invention.

FIG. 33 depicts a chart demonstrating the arterial blood gas profile foran organ under going perfusion according to an embodiment of theinvention.

FIG. 34 depicts a chart demonstrating adequate perfusion in a transplantorgan.

FIG. 35 depicts a chart demonstrating inadequate perfusion in atransplant organ.

ILLUSTRATIVE DESCRIPTION

As described above in summary, the invention generally provides improvedapproaches to ex-vivo organ care. More particularly, in variousembodiments, the invention is directed to improved systems, methods anddevices relating to maintaining an organ in an ex-vivo portableenvironment. According to one improvement, the organ preservation systemof the invention maintains a heart beating at or near normalphysiological conditions. To this end, the system circulates anoxygenated, nutrient enriched perfusion fluid to the heart at nearphysiological temperature, pressure and flow rate. According to oneimplementation, the system employs a perfusion fluid solution that moreaccurately mimics normal physiologic conditions. In one embodiment, theperfusion fluid is blood-product based. In alternative embodiments, thesolution is synthetic blood substitute based. In other embodiments thesolution may contain a blood product in combination with a bloodsubstitute product.

According to various illustrative embodiments, the improvements of theinvention enable an organ, such as a heart, to be maintained ex-vivo forextended periods of time, for example, exceeding 3, 4, 5, 6, 8, 10, 12,14, 16, 18, 20, 22, 24 or more hours. Such extended ex-vivo maintenancetimes expand the pool of potential recipients for donor organs, makinggeographical distance between donors and recipients less important.Extended ex-vivo maintenance times of the invention also provide thetime needed for better genetic and HLA matching between donor organs andorgan recipients, increasing the likelihood of a favorable outcome. Theability to maintain the organ in a near physiologic functioningcondition also enables a clinician to evaluate the organ's functionex-vivo, further increasing the likelihood of transplantation success.In some instances, the extended maintenance time enables medicaloperators to perform repairs on donor organs with minor defects.According to another advantage, the increased ex-vivo organ maintenancetimes of the invention enable an organ to be removed from a patient,treated in isolation ex-vivo, and then put back into the body of apatient. Such treatment may include, without limitation, surgicaltreatments, chemo-, bio-, gene and/or radiation therapies.

The illustrative systems, methods and devices of the invention aredescribed below in the following order. First, the components of anillustrative organ care system 100 are described. Second, illustrativeoperation of the system 100 is discussed. Third, a subset of thecomponents of the system 100 are described in further detail. Fourth,illustrative control systems and methods for the system 100 arediscussed. Fifth, an illustrative user interface is described. Sixth,mechanical features of the system 100 are discussed in further detailwith regard to an exemplary implementation. Seventh, exemplary methodsfor employing the system 100 during an organ harvest, transport, andtransplantation procedure are described. Eighth, illustrative perfusion,nutritional and preservative solutions suitable for use with the system100 are presented.

Turning to the illustrative embodiments, FIG. 1 depicts a schematicdiagram of a portable organ care system 100 according to an illustrativeembodiment of the invention. FIG. 2 shows a conceptual drawing of aheart 102, which may be preserved/maintained ex-vivo by the organ caresystem 100 of the invention. Referring to FIGS. 1 and 2 , theillustrative system 100 includes an organ chamber assembly 104 forcontaining the heart 102 during ex-vivo maintenance, a reservoir 160 forholding, defoaming and filtering the perfusion fluid 108, portal 774 forloading perfusion fluid 108 into the reservoir 160 and a portal 762 forapplying therapeutics to the fluid 108 contained in the reservoir 160, aperfusion fluid pump 106 for pumping/circulating perfusion fluid 108 toand from the harvested heart 102; a heater assembly 110 for maintainingthe temperature of the perfusion fluid 108 at or near physiologicaltemperatures; a flow mode selector valve 112 for switching betweennormal and retrograde aortic flow modes (also referred to as “normalflow mode” and “retrograde flow mode,” respectively); an oxygenator 114for re-oxygenating the perfusion fluid 108 subsequent to it beingexpelled by the heart 102; a nutritional subsystem 115 for replenishingnutrients 116 in the perfusion fluid 108 as they are metabolized by theheart 102 and for providing additional preservatives 118 to theperfusion fluid to reduce, for example, ischemia and/or otherreperfusion related injuries to the heart 102. The illustrative system100 also includes a plurality of sensors, including without limitation:temperature sensors 120, 122 and 124; pressure sensors 126, 128, 130 and132; perfusion flow rate sensors 134, 136 and 138; a perfusion fluidoxygenation sensor 140; and sensor electrodes 142 and 144, anddefibrillation source 143. The system 100 further includes: variouscomponents employed for maintaining suitable flow conditions to and fromthe heart 102; an operator interface 146 for assisting an operator inmonitoring operation of the system 100, and the condition of the heart102, and for enabling the operator to select various operatingparameters; a power subsystem 148 for providing fault tolerant power tothe system 100; and a controller 150 for controlling operation of theorgan care system 100.

Referring also to FIGS. 3 and 4 , according to the illustrativeembodiment, the system 100 can maintain the heart 102 in two modes ofoperation—a normal flow mode, shown in FIG. 3 , and a retrograde flowmode shown in FIG. 4 . Generally, in the normal flow mode of FIG. 3 ,the system 100 circulates the perfusion fluid 108 to the heart 102 inthe same manner as blood would circulate in the human body. Moreparticularly, referring to FIGS. 1-3 , the perfusion fluid enters theleft atrium 152 of the heart 102 via the pulmonary vein 168. Theperfusion fluid 108 is flowed away from the right ventricle 154 via thepulmonary artery 164 and away from the left 156 ventricle via the aorta158. In normal flow mode, the system 100 pumps the perfusion fluid tothe heart 102 at a near physiological rate of between about 1 liter/minand about 5 liters/minute. This mode is useful, for example, forperforming functional testing to verify that the heart 102 is defectfree, both prior and subsequent to transportation to a donor location.

Alternatively, in retrograde flow mode, shown in FIG. 4 , the system 100flows the perfusion fluid 108 into the heart 102 via the aorta 158,through the coronary sinus 155 and other coronary vasculature of theheart, and out of the right ventricle 154 of the heart 102 via thepulmonary artery 164. As discussed in further detail below with regardto FIGS. 24A and 24B, the system 100 also provides a trickle flow 769 tothe left atrium 152 through trickle valve 768. The trickle flow isprovided in an amount sufficient to moisten the left atrium 152 and leftventricle 156. In certain applications the trickle flow is less thanabout 5 ml/min, less than about 1 ml/min, or less than about 0.1 ml/min.In this mode of operation, the system 100 reduces the flow rate of theperfusion fluid 108 to between about 300 milliliters/minute and about 1liter/minute. The inventors have found that the retrograde flow path ofFIG. 4 , along with the reduced flow rate, reduces damage to the heart102 during extended periods of ex-vivo maintenance. Thus, according toone feature of the invention, the heart 102 is transported to a donorsite in retrograde flow mode.

Having briefly described the normal and retrograde flow modes, thesystem 100 will next be described in further detail operationally.Referring once again to FIGS. 1-4 , in one practice, the heart 102 isharvested from a donor and cannulated into the organ chamber assembly104. The perfusion fluid 108 is prepared for use within system 100 bybeing loaded into the reservoir 160 via portal 774 and, optionally,being treated with therapeutics via portal 762. The pump 106 pumps theloaded perfusion fluid 108 from a reservoir 160 to the heater assembly110. The heater assembly 110 heats the perfusion fluid 108 to or near anormal physiological temperature. According to one embodiment, theheater assembly 110 heats the perfusion fluid to between about32.degree. C. and about 37.degree. C. The heater assembly 110 has aninternal flow channel with a cross-sectional flow area that isapproximately equal to the inside cross-sectional area of fluid conduitsthat carry the perfusion fluid 108 into and/or away from the heaterassembly 110, so as to minimize disturbance of fluid flow. From theheater assembly 110, the perfusion fluid 108 flows to the flow modeselector valve 112.

Initially, the flow mode selector valve 112 is positioned in retrogrademode to direct the perfusion fluid 108 from the heater assembly 110 intothe organ chamber assembly 104 via a first interface 162. Also referredto as an aorta interface or left ventricle interface, the interface 162includes cannulation to vascular tissue of the left ventricle via anaperture 228 b located on the organ chamber assembly 104 (as shown inFIGS. 5A-5B). As the heart 102 warms, it begins to beat which causes theheart 102 to pump the perfusion fluid 108 through the coronaryvasculature 155 and out of the heart 102 through the right ventricle 154via a second interface 166. The second interface 166, also referred toas a pulmonary artery interface or a right ventricle interface, includescannulation to vascular tissue of the right ventricle via an aperture228 c located on the organ chamber assembly 104 (as shown in FIGS.5A-5B). As mentioned above, in retrograde flow mode, fluid is notactively pumped into or out of the left side of the heart, except for arelatively small trickle 769 of perfusion fluid, which is delivered tomoisten the left atrium 152 and left ventricle 156, as described belowin reference to FIGS. 24A-24E.

In response to the flow mode selector valve 112 being placed in thenormal mode position, it directs the perfusion fluid 108 into the leftatrium 152 of the heart 102 via a third interface 170. The thirdinterface 170, also referred to as a pulmonary vein interface or leftatrium interface, includes cannulation to vascular tissue of the leftatrium 152 via an aperture 228 a located on the organ chamber assembly104 (as shown in FIGS. 5A-5B). The heart 102 then expels the perfusionfluid 108 through the left ventricle 156 via the aorta interface 162 andthrough the right ventricle 154 via the pulmonary artery interface 166.

Each of the interfaces 162, 166 and 170 may be cannulated to the heart102 by pulling vascular tissue (e.g., an aorta stub) over the end of theinterface, then tying or otherwise securing the tissue to the interface.The vascular tissue is preferably a short segment of a blood vessel(e.g., an aorta stub 158) that remains connected to the heart 102 afterthe heart 102 is severed and explanted from the donor. For example, theaorta interface 162 is cannulated to a small segment of the severedaorta 158 which has been formed by severing the aorta 158 in a locationdownstream from the coronary sinus 155. In certain applications, theshort vessel segments may be about 5 to about 10 inches in length orlonger. The segments may also be shorter than about 5 inches. Thesegments may be about 2 to about 4 inches in length, or about 1 to about2 inches in length; in other applications the segments may be less thanabout ½ inch, or less than about ¼ inch.

Alternatively, the cannulation may occur by affixing the interfacedirectly to the applicable atrium or ventricle, as may be preferred inapplications where the heart 102 is prepared for explantation bysevering an entire blood vessel without leaving any stub portion of thevessel connected to the heart 102. For example, a left atrium 152cannulation can be formed by inserting the interface 170 directly intothe left atrium 152 and clamping the interface 170 in place, without theneed to tie to any pulmonary vein 168 tissue.

With continued reference to FIG. 1 , in both flow modes the perfusionfluid 108 flows from the pulmonary artery interface 166 into theoxygenator 114. The oxygenator 114 receives gas from an external oronboard source 172 through a gas regulator 174 and a gas flow chamber176, which can be a pulse-width modulated solenoid valve that controlsgas flow, or any other gas control device that allows for precisecontrol of gas flow rate. A gas pressure gauge 178 provides a visualindication of how full the gas supply 172 is. The transducer 132provides similar information to the controller 150. The controller 150can regulate automatically the gas flow into the oxygenator 114 independence, for example, on the perfusion fluid oxygen content measuredat the sensor 140. According to various illustrative embodiments, theoxygenator 114 is a standard membrane oxygenator, such as the Liliput 2manufactured by Dideco, a division of Sorin Biomedical, or the MINIMAXPLUS™ manufactured by Medtronic, Inc. In the illustrative embodiment,the gas includes an oxygen and carbon dioxide mixture. An exemplarycomposition of such a mixture contains about 85% O.sub.2, about 1%CO.sub.2, with the balance being N.sub.2. Subsequent to re-oxygenation,the oxygenator 114 returns the perfusion fluid 108 to the reservoir 160.According to the illustrative embodiment, the sensor 140 measures theamount of light absorbed or reflected by the perfusion fluid 108 whenapplied at a multi-wavelength to provide an optical-based measurement ofoxygen saturation. Since the perfusion fluid 108 is blood product basedin certain embodiments, it may contain red blood cells (i.e., oxygencarrying cells). Accordingly, the sensor 140 also provides a signal 145indicative of a hematocrit measurement of the perfusion fluid 108. Inalternative embodiments the solution 108 is formed of a synthetic bloodsubstitute, while in other embodiments, the solution 108 may contain ablood product in combination with a blood substitute product.

Also, in both flow modes, the nutritional subsystem 115, including asupply of maintenance solutions 116/118 and an infusion pump 182,infuses the perfusion fluid 108 with nutrients 116, such as glucose, asthe perfusion 108 solution flows through the system 100, and in someembodiments, while it is in the reservoir 160. The maintenance solutions116/118 also include a supply of therapeutics and preservatives 118 forreducing ischemia and other reperfusion related injuries to the heart102.

Both normal and retrograde flow modes are described in further detailbelow with reference to FIGS. 24A-26B.

According to the illustrative embodiment, the system 100 is primed priorto introducing an organ into the organ chamber assembly 104. Duringpriming, a priming solution (described below) is inserted into the organchamber 160 and pumped through the system 100. In one exemplarapplication, the priming occurs for a period of between about 5 andabout 20 minutes. The cannulation interfaces 162, 166 and 170 in theorgan chamber assembly 104 are bypassed to enable normal mode flow ofperfusion fluid 108 through the system 100, without the donor heart 102being present. Blood (or a synthetic blood substitute) is then loadedinto the reservoir 160. The blood may be the blood exsanguinated fromthe donor during harvesting of the heart 102 or obtained from typed andcross-matched banked blood. The system 100 then circulates the blood (orblood substitute) through the system 100 to heat, oxygenate, and filterit. Nutrients, preservatives and/or other therapeutics are provided viathe infusion pump 182 of the nutritional subsystem 115. Variousparameters may also be initialized and calibrated via the operatorinterface 146 during priming. Once the system 100 is runningappropriately, the pump rate can be decreased or brought to zero, andthe heart 102 can be cannulated into the organ chamber assembly 104. Thepump rate can then be increased. Priming of the system 100 is describedin further detail below with reference to the flow diagram of FIG. 29A.

As shown in FIG. 1 , the system 100 also includes a plurality ofcompliance chambers 184, 186 and 188. The compliance chambers 184, 186and 188 are essentially small inline fluid accumulators with flexible,resilient walls designed to simulate the human body's vascularcompliance by aiding the system in more accurately mimicking blood flowin the human body, for example, by providing flow back-pressure and/orby filtering/reducing fluid pressure spikes due, for example, to flowrate changes and/or the pumping of the pump 106. According to theillustrative embodiment, the compliance chamber 184 is located betweenan output 112 a of the mode valve 112 and the reservoir 160 and operatesin combination with an adjustable clamp 190 during normal flow mode toprovide back pressure to the aorta 158 to cause perfusion fluid to flowinto the coronary sinus 155 to feed the heart 102. In the illustrativeembodiment, the fluid back-pressure provided to the aorta 158 is betweenabout 55 mmHg and about 85 mmHg, which is within an acceptablenear-physiologic range of mean aortic blood pressure (which is typicallybetween about 80 mmHg and about 100 mmHg). The back pressure to theaorta 158 aids the system 100 in simulating normal physiologicconditions. The compliance chamber 186 is located between an output 112b of the mode valve 112 and the pulmonary vein cannulation interface 170of the organ chamber assembly 104. The primary function of thecompliance chamber 186 is to provide back-pressure to the left atrium152 and to smooth pressure/flow spikes caused from the pumping action ofthe perfusion fluid pump 106, which delivers blood to the heart withoutcausing substantial fluid pressure spikes. In the illustrativeembodiment, the fluid back-pressure provided to the left atrium 152 isbetween about 0 mmHg to about 14 mmHg, which is approximately the sameas the left atrial pressure under normal physiologic conditions. Thecompliance chamber 188 is located between an output of a one way valve310 and an inlet 110 a of the heater 110. The primary function of thecompliance chamber 188 is also to smooth pressure/flow spikes caused bythe pumping action of the perfusion fluid pump 106 and to provide fluidback-pressure to the pulmonary artery 164. In the illustrativeembodiment, the fluid back-pressure provided to the pulmonary artery 164is between about 0 mmHg and about 25 mmHg, which is within an acceptablenear-physiologic range of mean arterial blood pressure (between about 0mmHg and about 12 mmHg).

The compliance chambers 184, 186 and 188 provide the benefits describedabove through their size and shape and the materials used in theirdesign. The chambers 184, 186 and 188 are sized to contain about 20 mlto about 100 ml of fluid 108, and they are shaped in an ovalconfiguration to allow them to receive fluid 108 and expand to dampenpressure spikes and to provide back-pressure to the heart 102. Incertain applications, the material used for the chambers 184, 186 and188 includes at least one flexible membrane, selected so that thechambers have a Shore A durametric hardness (ASTM D2240 00) of about 10(more flexible) to about 60 (less flexible), with certain preferredembodiments having a hardness of between about 30 (± about 8) and about50 (± about 8). In the illustrative embodiment, the compliance chamber184 has a Shore A hardness of about 50 (± about 8) and the compliancechamber 186 has a Shore A hardness of about 30 (± about 8). In theillustrative embodiment, the compliance chamber 188 has a dual-layeredconfiguration, with an inner chamber having a Shore A hardness of about50 (± about 8) and an outer sleeve having a Shore A hardness of about 30(± about 8). Alternatively, the inner chamber can have a lower hardness(e.g., about 30, ± about 8) and outer sleeve can have a higher hardness(e.g., about 50, ± about 8)).

Having provided an operational overview of the system 100, the organchamber assembly 104, the perfusion heater assembly 110, and a pump headinterface assembly 192 for interfacing with the pump 106 are nextdescribed in further detail. FIGS. 5A-5F depict various views of theillustrative organ chamber assembly 104 of FIG. 1 . As shown mostclearly in FIGS. 5A-5D, the organ chamber assembly 104 includes ahousing 194, a outer lid 196 and an intermediate lid 198. The housingincludes a bottom 194 e and one or more walls 194 a-194 d for containingthe heart 102. The intermediate lid 198 covers an opening 200 to thehousing 194 for substantially enclosing the heart 102 within the housing194. As most clearly shown in FIGS. 5E and 5F, the intermediate lid 198includes a frame 198 a and a flexible membrane 198 b suspended withinthe frame 198 a. The flexible membrane 198 b, preferably, is transparentbut may be opaque, translucent, or substantially transparent. Accordingto one feature, the flexible membrane includes sufficient excessmembrane material to contact the heart 102 when contained within thehousing 195. This feature enables a medical operator to touch/examinethe heart 102 indirectly through the membrane 198 b, or apply anultrasound probe to the heart 102 through the membrane 198 b, whilemaintaining sterility of the housing 195. The membrane 198 b may bemade, for example, from any suitable flexible polymer plastic, forexample polyurethane. The membrane 198 b may also have integratedelectrically conductive pads/contacts 199 a and 199 b through whichelectrical activity of the heart may be sensed via electrodes such asthe electrodes 142 and 144, and/or for through which defibrillation orpacing signals may be delivered, as described more fully below.Alternatively, the contacts 199 a and 199 b may be electrodes includingall or a portion of the functionality of the electrodes 142 and 144. Asshown in FIG. 5C, the outer lid 196 opens and closes over theintermediate lid 198 independently from the intermediate lid 198.Preferably, the outer lid 196 is rigid enough to protect the heart 102from physical contact, indirect or indirect. The outer lid 196 and thechamber 194 may also be made from any suitable polymer plastic, forexample polycarbonate.

According to one implementation, the housing 194 includes two hingesections 202 a and 202 b, and the intermediate lid frame 198 a includestwo corresponding mating hinge sections 204 a and 204 b, respectively.The hinge sections 202 a and 202 b on the housing 194 interfit with thehinge sections 204 a and 204 b on the intermediate lid frame 198 a toenable the intermediate lid 198 to open and close relative to theopening 200 of the housing 194. As shown most clearly in FIGS. 5D and5F, the organ chamber assembly 104 also includes two latches 206 a and206 b for securing the intermediate lid 198 closed over the opening 200.As shown in FIGS. 5E and 5F, the latches 206 a and 206 b rotatably snapfit onto latch hinge section 208 a and 208 b, respectively, on the wall194 c of the housing 194. As shown most clearly in FIGS. 5A and 5E, theintermediate lid frame 198 a also includes a hinge section 210. Thehinge section 210 rotatably snap fits with a mating hinge section 212 onthe outer lid 196 to enable the outer lid 196 to open without openingthe intermediate lid 198. As shown best in FIGS. 5B, 5D and 5F, theouter lid 196 also includes two cutouts 214 a and 214 b for enabling thelatches 206 a and 206 b. to clamp down on the edge 216 of theintermediate lid frame 198 a. As shown in FIGS. 5B, 5D and 5F, the organchamber assembly 104 also includes a latch 218, which rotatably snapfits onto a hinge part 220 on the wall 194 c of the housing 194. Inoperation, the latch 218 engages a tab 221 on the edge 225 of the outerlid 196 to secure the outer lid 196 closed over the intermediate lid198.

As shown most clearly in FIGS. 5E and 5F, the intermediate lid alsoincludes two gaskets 198 c and 198 d. The gasket 198 d interfits betweena periphery of the intermediate lid frame 198 a and a periphery of theouter lid 196 to form a fluid seal between the intermediate lid 198 andthe outer lid 196 when the outer lid 196 is closed. The gasket 198 cinterfits between an outer rim 194 f of the housing 194 and theintermediate lid frame 198 a to form a fluid seal between theintermediate lid 198 and the periphery 194 f of the housing 194 when theintermediate lid 198 is closed.

Optionally, the organ chamber assembly 104 includes a pad 222 or a sacassembly sized and shaped for interfitting over an inner bottom surface194 g of the housing 194. Preferably, the pad 222 is formed from amaterial resilient enough to cushion the heart 102 from mechanicalvibrations and shocks during transport, for example a closed-cell foam.According to one feature, the pad 222 includes a mechanism foradjustably positioning a pair of electrodes, such as the electrodes 142and 144 of FIG. 1 . According to the illustrative embodiment, themechanism includes two through-apertures 224 a and 224 b for passingelectrical leads from the under side of the pad 222 to correspondingelectrodes 142 and 144 on the heart-contacting surface of the pad.Passing the electrical leads through the pad 222 to the electrodes 142and 144 enables the electrodes 142 and 144 to be adjustably positionedwithin the pad 222 to accommodate variously sized hearts. In otherembodiments, the mechanism may include, without limitation, one or moredifferently oriented slots, indentations, protrusions, throughapertures, partially through apertures, hooks, eyelets, adhesivepatches, or the like. In certain embodiments, the pad 222 may beconfigured with one or more sleeve-like structures that allow anelectrode to be inserted within the pad 222, thus providing amembrane-like surface of the pad 222 positioned between the electrodeand the heart 102.

In some illustrative embodiments, the pad 222 is configured as a padassembly, with the assembly including one or more electrodes, such asthe electrodes 142 and 144, adjustably located in or on the pad 222.According to one advantage, the pad/electrode configuration of theinvention facilitates contact between the electrodes and the heart 102placed on the pad 222, without temporarily or permanently suturing orotherwise mechanically connecting the electrodes to the heart 102. Theweight of the heart 102 itself can also help stabilize the electrodesduring transport. According to the illustrative embodiment, theelectrodes 142 and 144 include one or more sensors for monitoring one ormore electrical signals from the heart and/or defibrillators forproviding an electrical signal to the heart. As shown in FIGS. 1 and 5C,the organ chamber assembly 104 includes electrical interface connections235 a-235 b, which mount into the apertures 234 a-234 b, respectively,in the wall 194 b of the housing 194. A cover 226 is provided forprotecting the electrical interface connections 235 a-235 b when notbeing used.

As described below in further detail with reference to FIG. 15 , theinterface connections 235 a and 235 b couple electrical signals, such asECG signals, from the electrodes 142 and 144 out of the housing 194, forexample, to the controller 194 and/or the operator interface 146. Asdescribed in further detail below with reference to FIG. 22A, theinterface connections 235 a and 235 b may also couple to adefibrillation source, which may be either provided by externalinstrumentation or through circuitry within the system 100, and whichcan send a defibrillation or pacing signal 143 through electrodes 142and 144 to the heart 102.

As shown most clearly in FIGS. 5E and 5F, the organ chamber assembly 104includes a resealable membrane interface 230, which mounts in aninterface aperture 232. The interface 230 includes a frame 230 a and aresealable polymer membrane 230 b mounted in the frame 230 a. Themembrane 230 b may be made of silicone or any other suitable polymer. Inoperation, the interface 230 is used to provide pacing leads, whennecessary, to the heart 102, without having to open the chamber lids 196and 198. The membrane 230 b seals around the pacing leads to maintain aclosed environment around the heart 102. The membrane 230 b also resealsin response to removing the pacing leads.

As shown in FIGS. 5A and 5B, the organ chamber assembly 104 includesapertures 228 a-228 c for receiving the aorta interface 162, thepulmonary artery interface 166 and the pulmonary vein interface 170,described above with reference to FIGS. 1-4 , and below with referenceto FIGS. 24A-28C. As shown in FIG. 5D, the organ chamber assembly 104also includes a drain 201 for draining perfusion fluid 108 out of thehousing 194 back into the reservoir 160, and mounting receptacles203A-203 d for mounting the organ chamber assembly 104 onto the singleuse module (shown at 634 in FIG. 19A).

FIGS. 6A-6F depict various views of the perfusion fluid heater assembly110 of FIG. 1 . As shown in FIGS. 6A and 6B, the heater assembly 110includes a housing 234 having an inlet 110 a and an outlet 110 b. Asshown in both the longitudinal cross-sectional view of FIG. 6D and thelateral cross-sectional view of FIG. 6E, the heater assembly 110includes a flow channel 240 extending between the inlet 110 a and theoutlet 110 b. The heater assembly 110 may be conceptualized as havingupper 236 and lower 238 symmetrical halves. Accordingly, only the upperhalf is shown in an exploded view in FIG. 6F.

Referring now to FIGS. 6D-6F, the flow channel 240 is formed betweenfirst 242 and second 244 flow channel plates. The inlet 110 a flows theperfusion fluid into the flow channel 240 and the outlet 110 b flows theperfusion fluid out of the heater 110. The first 242 and second 244 flowchannel plates have substantially bioinert perfusion fluid 108contacting surfaces (which may contain a blood-product in certainembodiments) for providing direct contact with the perfusion fluidflowing through the channel 240. The fluid contacting surfaces may beformed from a treatment or coating on the plate or may be the platesurface itself. The heater assembly 110 includes first and secondelectric heaters 246 and 248, respectively. The first heater 246 islocated adjacent to and couples heat to a first heater plate 250. Thefirst heater plate 250, in turn, couples the heat to the first flowchannel plate 242. Similarly, the second heater 248 is located adjacentto and couples heat to a second heater plate 252. The second heaterplate 252 couples the heat to the second flow channel plate 244.According to the illustrative embodiment, the first 250 and second 252heater plates are formed from a material, such as aluminum, thatconducts and distributes heat from the first 246 and second 248 electricheaters, respectively, relatively uniformly. The uniform heatdistribution of the heater plates 250 and 252 enables the flow channelplates to be formed from a bioinert material, such as titanium, reducingconcern regarding its heat distribution characteristic.

Referring particularly to FIGS. 6E and 6F, the heater assembly 110 alsoincludes O-rings 254 and 256 for fluid sealing respective flow channelplates 242 and 244 to the housing 234 to form the flow channel 240.

The heater assembly 110 further includes first assembly brackets 258 and260. The assembly bracket 258 mounts on the top side 236 of the heaterassembly 110 over a periphery of the electric heater 246 to sandwich theheater 246, the heater plate 250 and the flow channel plate 242 betweenthe assembly bracket 258 and the housing 234. The bolts 262 a-262 j fitthrough corresponding through holes in the bracket 258, electric heater246, heater plate 250 and flow channel plate 242, and thread intocorresponding nuts 264 a-264 j to affix all of those components to thehousing 234. The assembly bracket 260 mounts on the bottom side 238 ofthe heater assembly 110 in a similar fashion to affix the heater 248,the heater plate 252 and the flow channel plate 244 to the housing 234.A resilient pad 268 interfits within a periphery of the bracket 258.Similarly, a resilient pad 270 interfits within a periphery of thebracket 260. A bracket 272 fits over the pad 268. The bolts 278 a-278 finterfit through the holes 276 a-276 f, respectively, in the bracket 272and thread into the nuts 280 a-280 f to compress the resilient pad 268against the heater 246 to provide a more efficient heat transfer to theheater plate 250. The resilient pad 270 is compressed against the heater248 in a similar fashion by the bracket 274.

As mentioned with respect to FIG. 1 , and as also shown in FIG. 6A, theillustrative heater assembly 110 includes temperature sensors 120 and122 and dual-sensor 124. The dual sensor 124 in practice includes a dualthermistor sensor for providing fault tolerance, measures thetemperature of the perfusion fluid 108 exiting the heater assembly 110,and provides these temperatures to the controller 150. As described infurther detail below with respect to the heating subsystem 149 of FIG.13 , the signals from the sensors 120, 122 and 124 may be employed in afeedback loop to control drive signals to the first 246 and/or second248 heaters to control the temperature of the heaters 256 and 248.Additionally, to ensure that heater plates 250 and 252 and, therefore,the blood contacting surfaces 242 and 244 of the heater plates 250 and252 do not reach a temperature that might damage the perfusion fluid,the illustrative heater assembly 110 also includes temperaturesensors/lead wires 120 and 122 for monitoring the temperature of theheaters 246 and 248, respectively, and providing these temperatures tothe controller 150. In practice, the sensors attached to sensors/leadwires 120 and 122 are RTD (resistance temperature device) based. As alsodiscussed in further detail with respect to FIG. 13 , the signals fromthe sensors attached to sensors/lead wires 120 and 122 may be employedin a feedback loop to further control the drive signals to the first 246and/or second 248 heaters to limit the maximum temperature of the heaterplates 250 and 252. As a fault protection, there are sensors for each ofthe heaters 246 and 248, so that if one should fail, the system cancontinue to operate with the temperature at the other sensor.

As described in further detail below with respect to FIG. 13 , theheater 246 of the heater assembly 110 receives from the controller 150drive signals 281 a and 281 b (collectively 281) onto correspondingdrive lead 282 a. Similarly, the heater 248 receives from the controller150 drive signals 283 a and 283 b (collectively 283) onto drive lead 282b. The drive signals 281 and 283 control the current to, and thus theheat generated by, the respective heaters 246 and 248. Moreparticularly, as shown in FIG. 7 , the drive leads 282 a includes a highand a low pair, which connect across a resistive element 286 of theheater 246. The greater the current provided through the resistiveelement 286, the hotter the resistive element 286 gets. The heater 248operates in the same fashion with regard to the drive lead 282 b.According to the illustrative embodiments, the element 286 has aresistance of about 5 ohms. However, in other illustrative embodiments,the element may have a resistance of between about 3 ohms and about 10ohms. As discussed in more detail below with regard to FIGS. 11 and 13 ,the heaters 246 and 248 may be controlled independently by the processor150.

According to the illustrative embodiment, the heater assembly 110housing components are formed from a molded plastic, for example,polycarbonate, and weighs less than about one pound. More particularly,the housing 234 and the brackets 258, 260, 272 and 274 are all formedfrom a molded plastic, for example, polycarbonate. According to anotherfeature, the heater assembly is a single use disposable assembly.

In operation, the illustrative heater assembly 110 uses between about 1Watt and about 200 Watts of power, and is sized and shaped to transitionperfusion fluid 108 flowing through the channel 240 at a rate of betweenabout 300 ml/min and about 5 L/min from a temperature of less than about30.degree. C. to a temperature of at least about 37.degree. C. in lessthan about 30 minutes, less than about 25 minutes, less than about 20minutes, less than about 15 minutes or even less than about 10 minutes,without substantially causing hemolysis of cells, or denaturing proteinsor otherwise damaging any blood product portions of the perfusion fluid.

According to one feature, the heater assembly 110 includes housingcomponents, such as the housing 234 and the brackets 258, 260, 272 and274, that are formed from a polycarbonate and weighs less than about 5lb. In other embodiments, the heater assembly may weigh less than about4 lb, less than about 3 lb, less than about 2 lb, or even less thanabout 1 lb. In the illustrative embodiment, the heater assembly 110 hasa length 288 of about 6.6 inches, not including the inlet 110 a andoutlet 110 b ports, and a width 290 of about 2.7 inches. The heaterassembly 110 has a height 292 of about 2.6 inches. The flow channel 240of the heater assembly 110 has a nominal width 296 of about 1.5 inches,a nominal length 294 of about 3.5 inches, and a nominal height 298 ofabout 0.070 inches. The height 298 and width 296 are selected to providefor uniform heating of the perfusion fluid 108 as it passes through thechannel 240. The height 298 and width 296 are also selected to provide across-sectional area within the channel 240 that is approximately equalto the inside cross-sectional area of fluid conduits that carry theperfusion fluid 108 into and/or away from the heater assembly 110. Inone configuration, the height 298 and width 296 are selected to providea cross-sectional area within the channel 240 that is approximatelyequal to the inside cross-sectional area of the inlet fluid conduit 792(shown below with reference to FIG. 25C) and/or substantially equal tothe inside cross-sectional area of the outlet fluid conduit 794 (shownbelow with reference to FIG. 24E).

Projections 257 a-257 d and 259 a-259 d are included in the heaterassembly 110 and are used to receive a heat-activated adhesive forbinding the heating assembly to the multiple-use unit 650 (referenced inFIG. 20A).

FIGS. 8A-8C show various views of a pump interface assembly 300according to an illustrative embodiment of the invention. FIG. 9 shows aperspective view of a pump-driver end of the perfusion fluid pumpassembly 106 of FIG. 1 , and FIG. 10 shows the pump interface assembly300 mated with the pump-driver end of the perfusion fluid pump assembly106, according to an illustrative embodiment of the invention. Referringto FIGS. 8A-10 , the pump interface assembly 300 includes a housing 302having an outer side 304 and an inner side 306. The interface assembly300 includes an inlet 308 and an outlet 310. As shown most clearly inthe bottom view of FIG. 8B and the exploded view of FIG. 8C, the pumpinterface assembly 300 also includes inner 312 and outer 314 O-ringseals, two deformable membranes 316 and 318, a doughnut-shaped bracket320, and half-rings 319 a and 319 b that fit between the o-ring 314 andthe bracket 320. The half-rings 319 a and 319 b may be made of foam,plastic, or other suitable material.

The inner O-ring 312 fits into an annular track along a periphery of theinner side 306. The first deformable membrane 316 mounts over the innerO-ring 312 in fluid tight interconnection with the inner side 306 of thehousing 302 to form a chamber between an interior side of the firstdeformable membrane 316 and the inner side 306 of the housing 302. Asecond deformable membrane 318 fits on top of the first deformablemembrane 316 to provide fault tolerance in the event that the firstdeformable membrane 316 rips or tears. Illustratively, the deformablemembranes 316 and 318 are formed from a thin polyurethane film (about0.002 inches thick). However, any suitable material of any suitablethickness may be employed. Referring to FIGS. 8A and 8B, the bracket 320mounts over the second deformable membrane 318 and the rings 319 a and319 b and affixes to the housing 302 along a periphery of the inner side306. Threaded fasteners 322 a-322 i attach the bracket 320 to thehousing 302 by way of respective threaded apertures 324 a-324 i in thebracket 320. As shown in FIG. 8B, the outer O-ring 314 interfits into anannular groove in the bracket 320 for providing fluid tight seal withthe pump assembly 106. Prior to inserting O-ring 314 into the annulargroove in bracket 320, the half-rings 319 a and 319 b are placed in thegroove. The O-ring 314 is then compressed and positioned within theannular groove in bracket 320. After being positioned within the annulargroove, the O-ring 314 expands within the groove to secure itself andthe half-rings 319 a and 319 b in place.

The pump interface assembly 300 also includes heat stake points 321a-321 c, which project from its outer side 304. As described in furtherdetail below with reference to FIGS. 21A-21C and 24A-24C, the points 321a-321 c receive a hot glue to heat-stake the pump interface assembly 300to a C-shaped bracket 656 of the single use disposable module chassis635.

As shown in FIG. 8C, the fluid outlet 310 includes an outlet housing 310a, an outlet fitting 310 b, a flow regulator ball 310 c and an outletport 310 d. The ball 310 c is sized to fit within the outlet port 310 dbut not to pass through an inner aperture 326 of the outlet 310. Thefitting 310 b is bonded to the outlet port 310 d (e.g., via epoxy oranother adhesive) to capture the ball 310 c between the inner aperture326 and the fitting 310 b. The outlet housing 310 a is similarly bondedonto the fitting 310 b.

In operation, the pump interface assembly 300 is aligned to receive apumping force from a pump driver 334 of the perfusion fluid pumpassembly 106 and translate the pumping force to the perfusion fluid 108,thereby circulating the perfusion fluid 108 to the organ chamberassembly 104. According to the illustrative embodiment, the perfusionfluid pump assembly 106 includes a pulsatile pump having a driver 334(described in further detail below with regard to FIG. 9 ), whichcontacts the membrane 318. The fluid inlet 308 draws perfusion fluid108, for example, from the reservoir 160, and provides the fluid intothe chamber formed between the inner membrane 316 and the inner side 306of the housing 302 in response to the pump driver moving in a directionaway from the deformable membranes 316 and 318, thus deforming themembranes 316 and 318 in the same direction. As the pump driver movesaway from the deformable membranes 316 and 318, the pressure head of thefluid 108 inside the reservoir 160 causes the perfusion fluid 108 toflow from the reservoir 160 into the pump assembly 106. In this respect,the pump assembly 106, the inlet valve 191 and the reservoir 160 areoriented to provide a gravity feed of perfusion fluid 108 into the pumpassembly 106. At the same time, the flow regulator ball 310 c is drawninto the aperture 326 to prevent perfusion fluid 108 from also beingdrawn into the chamber through the outlet 310. It should be noted thatthe outlet valve 310 and the inlet valve 191 are one way valves in theillustrated embodiment, but in alternative embodiments the valves 310and/or 191 are two-way valves. In response to the pump driver 334 movingin a direction toward the deformable membranes 316 and 318, the flowregulator ball 310 c moves toward the fitting 310 b to open the inneraperture 326, which enables the outlet 310 to expel perfusion fluid 108out of the chamber formed between the inner side 306 of the housing 302and the inner side of the deformable membrane 316. A separate one-wayinlet valve 191, shown between the reservoir 160 and the inlet 308 inFIG. 1 , stops any perfusion fluid from being expelled out of the inlet308 and flowing back into the reservoir 160.

As discussed in further detail below with respect to FIGS. 18A-27B, incertain embodiments the organ care system 100 mechanically divides intoa disposable single-use unit (shown at 634 in FIGS. 19A-19C and 24A-25C)and a non-disposable multi-use unit (shown at 650 in FIG. 20A). In suchembodiments, the pump assembly 106 rigidly-mounts to the multiple usemodule 650, and the pump interface assembly 300 rigidly mounts to thedisposable single use module 634. The pump assembly 106 and the pumpinterface assembly 300 have corresponding interlocking connections,which mate together to form a fluid tight seal between the twoassemblies 106 and 300.

More particularly, as shown in the perspective view of FIG. 9 , theperfusion fluid pump assembly 106 includes a pump driver housing 338having a top surface 340, and a pump driver 334 housed within a cylinder336 of the housing 338 The pump driver housing 338 also includes adocking port 342, which includes a slot 332 sized and shaped for matingwith a flange 328 projecting from the pump interface assembly 300. Asshown in FIG. 10 , the top surface 340 of the pump driver housing 338mounts to a bracket 346 on the non-disposable multiple use module unit650. The bracket 346 includes features 344 a and 344 b for abutting thetapered projections 323 a and 323 b, respectively, of the pump interfaceassembly 300. The bracket 346 also includes a cutout 330 sized andshaped for aligning with the docking port 342 and the slot 332 on thepump driver housing 338.

Operationally, the seal between the pump interface assembly 300 and thefluid pump assembly 106 is formed in two steps, illustrated withreference to FIGS. 9 and 10 . In a first step, the flange 328 ispositioned within the docking port 342, while the tapered projections323 a and 323 b are positioned on the clockwise side next tocorresponding features 344 a and 344 b on the bracket 346. In a secondstep, as shown by the arrows 345, 347 and 349 in FIG. 9 , the pumpinterface assembly 300 and the fluid pump assembly 106 are rotated inopposite directions (e.g., rotating the pump interface assembly 300 in acounter clockwise direction while holding the pump assembly 106 fixed)to slide the flange 328 into the slot 332 of the docking port 342. Atthe same time, the tapered projections 323 a and 323 b slide under thebracket features 344 a and 344 b, respectively, engaging inner surfacesof the bracket features 344 a and 344 b with tapered outer surfaces ofthe tapered projections 323 a and 323 b to draw the inner side 306 ofthe pump interface assembly 300 toward the pump driver 334 and tointerlock the flange 328 with the docking ports 342, and the taperedprojections 323 a and 323 b with the bracket features 344 a and 344 b toform the fluid tight seal between the two assemblies 300 and 106.

Having described the illustrative organ care system 100 from a system,operational and component point of view, illustrative control systemsand methods for achieving operation of the system 100 are nextdiscussed. More particularly, FIG. 11 depicts a block diagram of anillustrative control scheme for the system 100. As described above withreference to FIG. 1 , the system 100 includes a controller 150 forcontrolling operation of the system 100. As shown, the controller 150connects interoperationally with the following six subsystems: anoperator interface 146 for assisting an operator in monitoring andcontrolling the system 100 and in monitoring the condition of the heart102; a data acquisition subsystem 147 having various sensors forobtaining data relating to the heart 102 and to the system 100, and forconveying the data to the controller 150; a power management subsystem148 for providing fault tolerant power to the system 100; a heatingsubsystem 149 for providing controlled energy to the heater 110 forwarming the perfusion fluid 108; a data management subsystem 151 forstoring and maintaining data relating to operation of the system 100 andwith respect to the heart 102; and a pumping subsystem 153 forcontrolling the pumping of the perfusion fluid 108 through the system100. It should be noted that although the system 100 is describedconceptually with reference to a single controller 150, the control ofthe system 100 may be distributed in a plurality of controllers orprocessors. For example, any or all of the described subsystems mayinclude a dedicated processor/controller. Optionally, the dedicatedprocessors/controllers of the various subsystems may communicate withand via a central controller/processor.

FIGS. 12-17J illustrate the interoperation of the various subsystems ofFIG. 11 .

Referring first to the block diagram of FIG. 12 , the data acquisitionsubsystem 147 includes sensors for obtaining information pertaining tohow the system 100 and the heart 102 is functioning, and forcommunicating that information to the controller 150 for processing anduse by the system 100. As described with respect to FIG. 1 , the sensorsof subsystem 147 include, without limitation: temperature sensors 120,122 and 124; pressure sensors 126, 128, and 130; flow rate sensors 134,136 and 138; the oxygenation/hematocrit sensor 140; and electrodes 142and 144. The data acquisition subsystem 147 also includes: a set of Hallsensors 388 and a shaft encoder 390 from the perfusion pump assembly106; battery sensors 362 a-362 c for sensing whether the batteries 352a-352 c, respectively, are sufficiently charged; an external poweravailable sensor 354 for sensing whether external AC power is available;an operator interface module battery sensor 370 for sensing a state ofcharge of the operator interface module battery; and a gas pressuresensor 132 for sensing gas flow from the gas flow chamber 176. How thesystem 100 uses the information from the data acquisition subsystem 147will now be described with regard to the heating 149, power management148, pumping 153, data management 151, and operator interface 146subsystems, shown in further detail in FIGS. 13-17J, respectively.

The heating subsystem 149 is depicted in the block diagram of FIG. 13 .With continued reference also to FIG. 1 , the heating subsystem 149controls the temperature of the perfusion fluid 108 within the system100 through a dual feedback loop approach. In the first loop 251 (theperfusion fluid temperature loop), the perfusion fluid temperaturethermistor sensor 124 provides two (fault tolerant) signals 125 and 127to the controller 150. The signals 125 and 127 are indicative of thetemperature of the perfusion fluid 108 as it exits the heater assembly110. The controller 150 regulates the drive signals 285 and 287 to thedrivers 247 and 249, respectively. The drivers 247 and 249 convertcorresponding digital level signals 285 and 287 from the controller 150to heater drive signals 281 and 283, respectively, having sufficientcurrent levels to drive the first 246 and second 248 heaters to heat theperfusion fluid 108 to within an operator selected temperature range. Inresponse to the controller 150 detecting that the perfusion fluidtemperatures 125 and 127 are below the operator-selected temperaturerange, it sets the drive signals 281 and 283 to the first 246 and second248 heaters, respectively, to a sufficient level to continue to heat theperfusion fluid 108. Conversely, in response to the controller 150detecting that the perfusion fluid temperatures 125 and 127 are abovethe operator-selected temperature range, it decreases the drive signals281 and 283 to the first 246 and second 248 heaters, respectively. Inresponse to detecting that the temperature of the perfusion fluid 108 iswithin the operator-selected temperature range, the controller 150maintains the drive signals 281 and 283 at constant or substantiallyconstant levels.

Preferably, the controller 150 varies the drive signals 281 and 283 insubstantially the same manner. However, this need not be the case. Forexample, each heater 246 and 248 may respond differently to a particularcurrent or voltage level drive signal. In such a case, the controller150 may drive each heater 246 and 248 at a slightly different level toobtain the same temperature from each. According to one feature, theheaters 246 and 248 each have an associated calibration factor, whichthe controller 150 stores and employs when determining the level of aparticular drive signal to provide to a particular heater to achieve aparticular temperature result. In certain configurations, the controller150 sets one of the thermistors in dual sensor 124 as the defaultthermistor, and will use the temperature reading from the defaultthermistor in instances where the thermistors give two differenttemperature readings. In certain configurations, where the temperaturereadings are within a pre-defined range, the controller 150 uses thehigher of the two readings. The drivers 247 and 249 apply the heaterdrive signals 281 and 283 to corresponding drive leads 282 a and 282 bon the heater assembly 110.

In the second loop 253 (the heater temperature loop), the heatertemperature sensors 120 and 122 provide signals 121 and 123, indicativeof the temperatures of the heaters 246 and 248, respectively, to thecontroller 150. According to the illustrated embodiment, a temperatureceiling is established for the heaters 246 and 248 (e.g., by default orby operator selection), above which the temperatures of the heaters 246and 248 are not allowed to rise. As the temperatures of the heaters 246and 248 rise and approach the temperature ceiling, the sensors 121 and123 indicate the same to the controller 150, which then lowers the drivesignals 281 and 283 to the heaters 246 and 248 to reduce or stop thesupply of power to the heaters 246 and 248. Thus, while a lowtemperature signal 125 or 127 from the perfusion fluid temperaturesensor 124 can cause the controller 150 to increase power to the heaters246 and 248, the heater temperature sensors 120 and 122 ensure that theheaters 246 and 248 are not driven to a degree that would cause theirrespective heater plates 250 and 252 to become hot enough to damage theperfusion fluid 108. According to various illustrative embodiments, thecontroller 150 is set to maintain the perfusion fluid temperature atbetween about 32.degree. C. and about 37.degree. C., or between about34.degree. C. and about 36.degree. C. According to a furtherillustrative embodiment, the controller 150 is set to limit the maximumtemperature of the heater plates 250 and 252 to less than about38.degree. C., 39.degree. C., 40.degree. C., 41.degree. C., or42.degree. C.

As can be seen, the second loop 253 is configured to override the firstloop 251, if necessary, such that temperature readings from temperaturesensors 120 and 122 indicating that the heaters 246 and 248 areapproaching the maximum allowable temperature override the effect of anylow temperature signal from the perfusion fluid temperature sensor 124.In this respect, the subsystem 149 ensures that the temperature of theheater plates 250 and 252 do not rise above the maximum allowabletemperature, even if the temperature of the-perfusion fluid 108 has notreached the operator-selected temperature value. This override featureis particularly important during failure situations. For example, if theperfusion fluid temperature sensors 124 both fail, the second loop 253stops the heater assembly 110 from overheating and damaging theperfusion fluid 108 by switching control exclusively to the heatertemperature sensors 120 and 122 and dropping the temperature set pointto a lower value. According to one feature, the controller 150 takesinto account two time constants assigned to the delays associated withthe temperature measurements from the heaters 246 and 248 and perfusionfluid 108 to optimize the dynamic response of the temperature controls.

FIG. 14 depicts a block diagram of the power management system 148 forproviding fault tolerant power to the system 100. As shown, the system100 may be powered by one of four sources—by an external AC source 351(e.g., 60 Hz, 120 VAC in North America or 50 Hz, 230 VAC in Europe) orby any of three independent batteries 352 a-352 c. The controller 150receives data from an AC line voltage availability sensor 354, whichindicates whether the AC voltage 351 is available for use by the system100. In response to the controller 150 detecting that the AC voltage 351is not available, the controller 150 signals the power switchingcircuitry 356 to provide system power high 358 from one of the batteries352 a-352 c. The controller 150 determines from the battery chargesensors 362 a-362 c which of the available batteries 352 a-352 c is mostfully charged, and then switches that battery into operation by way ofthe switching network 356.

Alternatively, in response to the controller 150 detecting that theexternal AC voltage 351 is available, it determines whether to use theavailable AC voltage 351 (e.g., subsequent to rectification) forproviding system power 358 and for providing power to the user interfacemodule 146, for charging one or more of the batteries 352 a-352 c,and/or for charging the internal battery 368 of user interface module146, which also has its own internal charger and charging controller. Touse the available AC voltage 351, the controller 150 draws the ACvoltage 351 into the power supply 350 by signaling through the switchingsystem 364. The power supply 350 receives the AC voltage 351 andconverts it to a DC current for providing power to the system 100. Thepower supply 350 is universal and can handle any line frequencies orline voltages commonly used throughout the world. According to theillustrative embodiment, in response to a low battery indication fromone or more of the battery sensors 362 a-362 c, the controller 150 alsodirects power via the switching network 364 and the charging circuit 366to the appropriate battery. In response to the controller 150 receivinga low battery signal from the sensor 370, it also or alternativelydirects a charging voltage 367 to the user interface battery 368.According to another feature, the power management subsystem 148 selectsbatteries to power the system 100 in order of least-charged first,preserving the most charged batteries. If the battery that is currentlybeing used to power the system 100 is removed by the user, the powermanagement subsystem 148 automatically switches over to the nextleast-charged battery to continue powering the system 100.

According to another feature, the power management subsystem 148 alsoemploys a lock-out mechanism to prevent more than one of the batteries352 a-352 c from being removed from the system 100 at a given time. Ifone battery is removed, the other two are mechanically locked intoposition within the system 100. In this respect, the system 148 providesa level of fault tolerance to help ensure that a source of power 358 isalways available to the system 100.

The pumping subsystem 153 of FIG. 11 will now be described in furtherdetail with reference to FIGS. 15 and 16 . More particularly, FIG. 15 isa conceptual block diagram depicting the illustrative pumping subsystem153, and FIG. 16 shows an exemplary ECG 414 of a heart 102 synchronizedwith an exemplary wave 385 depicting pumping output by the subsystem153. The ECG 414 shown in FIG. 16 has P, Q, R, S, T, and U peaks. Thepumping subsystem 153 includes the perfusion fluid pump 106interoperationally connected to the pump interface assembly 300, asdescribed in more detail above with reference to FIGS. 8A-10 . As shownin FIG. 15 , the controller 150 operates the pumping subsystem 153 bysending a drive signal 339 to a brushless three-phase pump motor 360using Hall Sensor feedback. The drive signal 339 causes the pump motorshaft 337 to rotate, thereby causing the pump screw 341 to move the pumpdriver 334 up and/or down. According to the illustrative embodiment, thedrive signal 339 is controlled to change a rotational direction androtational velocity of the motor shaft 337 to cause the pump driver 334to move up and down cyclically. This cyclical motion pumps the perfusionfluid 108 through the system 100.

In operation, the controller 150 receives a first signal 387 from theHall sensors 388 positioned integrally within the pump motor shaft 337to indicate the position of the pump motor shaft 337 for purposes ofcommutating the motor winding currents. The controller 150 receives asecond higher resolution signal 389 from a shaft encoder sensor 390indicating a precise rotational position of the pump screw 341. From thecurrent motor commutation phase position 387 and the current rotationalposition 389, the controller 150 calculates the appropriate drive signal339 (both magnitude and polarity) to cause the necessary rotationalchange in the motor shaft 337 to cause the appropriate vertical positionchange in the pump screw 341 to achieve the desired pumping action. Byvarying the magnitude of the drive signal 339, the controller 150 canvary the pumping rate (i.e., how often the pumping cycle repeats) and byvarying the rotational direction changes, the controller 150 can varythe pumping stroke volume (e.g., by varying how far the pump driver 334moves during a cycle). Generally speaking, the cyclical pumping rateregulates the pulsatile rate at which the perfusion fluid 108 isprovided to the heart 102, while (for a given rate) the pumping strokeregulates the volume of perfusion fluid 108 provided to the heart 102.

Both the rate and stroke volume affect the flow rate, and indirectly thepressure, of the perfusion fluid 108 to and from the heart 102. Asmentioned with regard to FIG. 1 , the system includes three flow ratesensors 134, 136 and 138, and three pressure sensors 126, 128 and 130.As shown in FIG. 15 , the sensors 134, 136, and 138 providecorresponding flow rate signals 135, 137 and 139 to the controller 150.Similarly, the sensors 126, 128 and 130 provide corresponding pressuresignals 129, 131 and 133 to the controller 150. The controller 150employs all of these signals in feedback to ensure that the commandsthat it is providing to the perfusion pump 106 have the desired effecton the system 100. In some instances, and as discussed below in furtherdetail with reference to FIGS. 17A-17J, the controller 150 may generatevarious alarms in response to a signal indicating that a particular flowrate or fluid pressure is outside an acceptable range. Additionally,employing multiple sensors enables the controller 150 to distinguishbetween a mechanical issue (e.g., a conduit blockage) with the system100 and a biological issue with the heart 102.

According to one feature of the invention, the pumping system 153 may beconfigured to control the position of the pump driver 334 during eachmoment of the pumping cycle to allow for finely tuned pumping rate andvolumetric profiles. This in turn enables the pumping system 153 tosupply perfusion fluid 108 to the heart with any desired pulsatilepattern. According to one illustrative embodiment, the rotationalposition of the shaft 337 is sensed by the shaft encoder 390 andadjusted by the controller 150 at least about 100 increments perrevolution. In another illustrative embodiment, the rotational positionof the shaft 337 is sensed by the shaft encoder 390 and adjusted by thecontroller 150 at least about 1000 increments per revolution. Accordingto a further illustrative embodiment, the rotational position of theshaft 337 is sensed by the shaft encoder 390 and adjusted by thecontroller 150 at least about 2000 increments per revolution. Thevertical position of the pump screw 341 and thus the pump driver 334 iscalibrated initially to a zero or a ground position, corresponding to areference position of the pump screw 341.

According to the illustrative embodiment, the positional precision ofthe pumping subsystem 153 enables the controller 150 to preciselyregulate the pumping of the perfusion fluid 108 through the heart 102.This process of synchronizing the pulsatile flow of the perfusion fluidto the heart's natural rate is referred to herein as “r-wavesynchronization,” which is described with continued reference to FIGS.2, 15, and 16 . A normally functioning heart has a two-phase pumpingcycle-diastole and systole. During the diastolic phase, also known asthe “resting phase,” the heart's atria 157 and 152 contract, causingvalves to open between the atria 157 and 152 and the ventricles 154 and156 to allow blood to flow into and load the ventricles 154 and 156.During the systolic phase, the loaded ventricles eject the blood, andthe atria 157 and 152 are opened and fill with blood. The cyclicalexpansion and contraction of the heart 102 during this process can berepresented by graphing the heart's ventricular ECG wave form, shown at414 in FIG. 16 . FIG. 16 depicts the ECG waveform 414 synchronized withan exemplary wave 385 representative of a pumping output by thesubsystem 153.

The pumping subsystem 153 is configured to provide the maximum output ata time that will result in delivery of fluid 108 to the heart 102 at themost beneficial time. In the illustrated embodiment, in retrograde mode,the pumping subsystem 153 is configured to pump fluid 108 toward theheart 102 so that the maximum pump output 382 occurs during thediastolic phase of the heart, which begins after the S peak shown inFIG. 16 and is when the left ventricle 156 has finished ejectingperfusion fluid 108 through the aorta 158. Timing the pump output inthis manner allows the user to maximize the injection of perfusion fluid108 through the aorta 158 and into the coronary sinus 155. The timedpumping is accomplished by starting the pumping at point 377 on wave385, which is a point prior to point 382 and corresponds to the peak ofthe heart's r-wave pulse 380 and the middle of ventricular systole. Thepoint 377 is selected to account for time-delay between the time asignal is provided from the controller 150 to start pumping the fluidand the time of actual delivery of the pumped fluid 108 to the heart102. In another example, during normal flow mode where the left sideof-the heart fills and ejects perfusion fluid (as described in moredetail with reference to FIG. 24A), the controller 150 synchronizes thepumping subsystem 153 to start pumping at a fixed period of time afterthe r-wave 380, so as to match the natural filling cycle of the leftatrium 152. The synchronization may be adjusted and fine-tuned by theoperator through a pre-programmed routine in the operating software onthe system 100 and/or by manually operating the controls of the userinterface display area 410, as described in more detail below inreference to FIGS. 17A-17J.

To achieve the synchronized pump output, the controller 150 predictswhen the heart's r-wave pulses 380 will occur and causes the pump topump at the appropriate time during the ECG 414. To make thisprediction, the controller 150 measures the length various r-wave pulses380 from the electrical signals 379 and 381 provided from the electrodes142 and 144, respectively. From these pulses, the controller 150 tracksthe time that elapses from one pulse 380 to the next, and uses thisinformation to calculate a running average of the length of timeseparating two sequential r-wave pulses. From this information, thecontroller 150 projects the time of the next r-wave (and from theprojection determines the time prior to or after that projected r-wavewhen the pumping should start to achieve optimal output delivery) byadding the average time separating two sequential r-wave pulses to thetime of the previous r-wave 380. Based on this running average ofseparation time between r-waves, the controller 150 has the option toadjust the time of pump output in relation to subsequent r-waves, asreflected in the movement of wave 385 to the left or the right along theECG 414 as signified by the arrow 383 in FIG. 16 . Adjusting the wave385 thus allows the user to adjust and customize the timing of output bythe pump 106 so as to optimize the filling of the heart. In addition,the pump 106 may also be adjusted to increase or decrease the pumpstroke volume to customize the volume of fluid 108 provided by the pump106, and this may be done either in concert with or independent of ther-wave synchronization.

It should be noted that although the subsystem 153 particularlysynchronizes with the r-wave cycle 385, this need not be the case. Inalternative illustrative embodiments, the subsystem 153 may pump insynchronicity with any available characteristic of the heart, includingfluid pressures into or out of a particular chamber or vessel. Also, thesubsystem 153 may be programmed to pump in any arbitrary pattern,whether periodic or not.

Referring back to FIG. 11 , the data management subsystem 151 receivesand stores data and system information from the various othersubsystems. The data and other information may be downloaded to aportable memory device and organized within a database, as desired by anoperator. The stored data and information can be accessed by an operatorand displayed through the operator interface subsystem 146.

Turning now to the operator interface subsystem 146, FIGS. 17A-17J showvarious illustrative display screens of the operator interface subsystem146. The display screens of FIGS. 17A-17J enable the operator to receiveinformation from and provide commands to the system 100. FIG. 17Adepicts a top level “home page” display screen 400 according to anillustrative embodiment of the invention. From the display screen 400 anoperator can access all of the data available from the data acquisitionsubsystem 147, and can provide any desired commands to the controller150. As described in more detail in reference to FIGS. 17B-17J, thedisplay screen 400 of FIG. 17A also allows the operator to access moredetailed display screens for obtaining information, providing commandsand setting operator selectable parameters.

With continued reference to FIG. 1 , the display screen 400 includes adisplay area 402, which shows a number of numerical and graphicalindications pertaining to the operation of the system 100. Inparticular, the display area 402 includes a numerical reading of theaorta output pressure (AOP) 404 of the perfusion fluid 108 exiting theaorta interface 162 on the organ chamber assembly 104, a wave formdepiction 406 of the aortic fluid pressure (AOP) 404, and an AOP alarmimage 408 indicating whether the fluid pressure 404 is too high or toolow (the alarm 408 is shown as “off” in FIG. 17A). The display screen400 also includes a display area 410 having a numerical indication 412of the rate at which the heart 102 is beating, an ECG 414 of the heart102, a heart rate (HR) alarm image 416 indicating whether the HR 412exceeds or falls below operator set thresholds, and a time log 418indicating how long the system 100 has been running, including primingtime (discussed in further detail below with reference to FIG. 29A). Anumerical display 419 shows the amount of time for which the system 100has been supporting the heart 102. The indicator alarm 413 indicateswhen an operator preset time limit is exceeded.

The display screen 400 includes a number of additional display areas420, 424, 432, 438, 444,450,456,460, 462, 466,472,480, and 482. Thedisplay area 420 shows a numerical reading of the pulmonary arterypressure (PAP) 422. The PAP 422 is an indication of the pressure of theperfusion fluid 108 flowing from the heart's pulmonary artery 164, asmeasured by the pressure sensor 130. The display area 420 also providesa PAP alarm indicator 424, which signals when the PAP 422 is outside anoperator preset range. The display area 426 indicates the temperature(Temp) 428 of the perfusion fluid 108 as it exits the heater 110. Thedisplay area 426 also includes a Temp alarm indicator 430, which signalsin response to the Temp 428 being outside of an operator preset range.The upper limit of the operator preset range is shown at 427. Thedisplay area 432 shows a numerical reading of the hematocrit (HCT) 434of the perfusion fluid 108, and an HCT alarm indicator 436 for signalingthe operator if the HCT 434 falls below an operator preset threshold.The display area 438 shows the oxygen saturation (SvO.sub.2) 440 of theperfusion fluid 108. The display area 438 also includes a SvO.sub.2alarm 442 for indicating if the SvO.sub.2 440 of the perfusion fluid 108falls below an operator preset threshold. The display area 444 indicatesthe aorta output flow rate (AOF) 446 of the perfusion fluid 108 as itflows out of the aorta 158. The AOF 446 is measured by the flow ratesensor 134. The AOF alarm 448 indicates whether the flow rate 446 fallsoutside of an operator preset range. The display area 450 shows theorgan chamber flow rate (CF) 452. The CF 452 is an indication of theflow rate of the perfusion fluid 108 as it exits the organ chamber 104,as measured by the flow rate sensor 136. The display area 450 alsoincludes a CF alarm 454, which signals in response to the CF 454 fallingoutside of an operator preset range. The display area 456 includes agraphic 458 for indicating when a file transfer to the memory card isoccurring.

The display area 460 shows a graphical representation 459 of the degreeto which each of the batteries 352 a-352 c (described above withreference to FIG. 14 ) is charged. The display area 460 also provides anumerical indication 461 of the amount of time remaining for which thebatteries 352 a-352 c can continue to run the system 100 in a currentmode of operation. The display area 462 identifies whether the operatorinterface module 146 is operating in a wireless 464 fashion, along witha graphical representation 463 of the strength of the wirelessconnection between the operator interface module 146 and the remainderof the system 100. The display area 462 also provides graphicalindication 467 of the charge remaining in the operator interface modulebattery 368 (described above with reference to FIG. 14 ) and a numericalindication 465 of the amount of time remaining for which the operatorinterface module battery 368 can support it in a wireless mode ofoperation. The display area 466 indicates the flow rate 468 of oxygenfrom the gas flow chamber 176. It also provides a graphical indication469 of how full an onboard oxygen tank is, and a numerical indication470 of the amount of time remaining before the onboard oxygen tank runsout. The display area 472 shows the heart rate of the heart 102, and theamount of time 476 for which the heart 102 has been cannulated onto thesystem 100. This field is duplicative of the field 419 mentioned above.The display areas 480 and 482 show the current time and date,respectively, of operation of the system 100.

Actuating a dial (or mouse, or other control device), such as the dial626 shown in FIG. 18A, on the operator interface 146 opens aconfiguration menu 484, such as shown in the display screen 401 of FIGS.17B. As shown, accessing the configuration menu 484 covers the displayareas 402 and 410 so they no longer show the graphical depictions of thepressure 406 and the heart rate 414, but continue to display criticalalpha/numeric information. As also shown, all other display areas remainunchanged. This enables an operator to adjust operation of the system100 while continuing to monitor critical information. According to onefeature, the configuration menu 484 allows the operator to pre-programdesired operational parameters for the system 100. Using the displayscreen 401, the operator can view/edit working and diastolic (orretrograde) mode alarms by selecting the fields 488 and 490,respectively. The operator can set particular ECG and LAP graphicaloptions by selecting the fields 492 and 494. Additionally, the operatorcan set oxygen flow rate and perfusion fluid temperature by selectingthe fields 496 and 498, respectively. Selecting the field 500 enablesthe operator to set the time and date, while selecting the field 502enables the operator to select the language in which information isdisplayed. At the bottom of the display field 484, the operator has theoption to return 504 to the display screen 400, cancel 506 any changesmade to operational settings, save 508 the changes as new defaults, orreset 510 the operational settings to factory defaults.

Referring to FIGS. 17C-17D, selecting the view/edit working mode alarmsfield 488 causes the working mode alarm dialog 512 of FIG. 17D to openwithin the display field 484 of FIG. 17C. The working mode dialog 512displays the parameters associated with normal flow mode (describedabove with reference to FIGS. 1 and 3 ) and includes a field for settingnumerical thresholds for each of the normal flow mode alarms. Morespecifically, the dialog 512 includes: CF alarm field 514; PAP alarmfield 516; AOP alarm field 518; LAP alarm field 520; perfusion fluidTemp alarm field 524; SvO.sub.2 alarm field 526; HCT alarm field 528;and HR alarm field 530. By selecting a particular alarm field andactuating the up 532 and/or down 534 arrows, a operator can adjust theacceptable upper and/or lower thresholds for each of the parametersassociated with each of the alarms. The dialog 512 also includes alarmgraphics 536 a-536 i, each of which being associated with a particularnormal flow mode alarm. The operator can enable/disable any of the abovenormal flow mode alarms by selecting the associated alarm graphic 536a-536 i. Any changes made using the dialog 512 are reflected incorresponding fields in the display screen 400 of FIG. 17A.

Referring to FIGS. 17A, 17B and 17E, selecting the view/edit non-workingmode alarms field 490 causes the resting mode alarm dialog 538 of FIG.17E to open within the display field 484 of FIG. 17C. The resting modedialog 538 displays the parameters associated with retrograde flow mode(described above with reference to FIGS. 1 and 4 ) and includes a fieldfor setting numerical thresholds for each of the retrograde flow modealarms. According to the illustrative embodiment, the available alarmsfor the normal and retrograde flow modes are similar, but notnecessarily the same. Additionally, even for those that are the same,the thresholds may differ. Accordingly, the invention enables theoperator to select different alarms and/or different thresholds for eachflow mode of operation. More specifically, the dialog 538 includes: CFalarm field 540; PAP alarm field 542; AOF alarm field 544; AOP alarmfield 546; LAP alarm field 548; perfusion fluid Temp alarm field 550;SvO.sub.2 alarm field 552; HCT alarm field 556; and HR alarm field 558.By selecting a particular alarm field and actuating the up 560 and/ordown 562 arrows, an operator can adjust the acceptable numerical upperand/or lower thresholds for each of the parameters associated with eachof the alarms. The dialog 538 also includes alarm graphics 564 a-564 i,each of which being associated with a particular normal flow mode alarm.The operator can enable/disable any of the above normal flow mode alarmsby selecting the associated alarm graphic 564 a-564 i. As is the case ofthe dialog 512, any changes, made using the dialog 538 are reflected incorresponding fields in the display screen 400 of FIG. 17A. In oneimplementation, the system 100 may be configured to automatically switchbetween sets of alarm limits for a given flow mode upon changing theflow mode.

Referring to FIGS. 17A, 17B, 17F and 17G, the operator interface 146also provides graphical mechanisms for adjusting various parameters. Forexample, as noted above in reference to FIG. 16 , one advantage of theuser display area 402 is that it allows the operator to monitor (andadjust) the pumping of the subsystem 153. Display area 410 identifiesthe ECG waveform 414 of the heart 102, and display 402 shows in waveform 406 the pressure of fluid flowing through the aorta. In these twodisplays the operator can monitor the effect of the pumping profile onthe heart's EGC 414, which allows the user to adjust the stroke volumeof the pumping subsystem 153, to adjust the rate of the pumpingsubsystem 153 (and thus the flow-rate of the fluid 108 being pumpedthrough the system 100), to manually impose, or adjust a time of, firingof the subsystem (e.g., by imposing a fixed delay between the r-wave 380and the beginning of the pumping cycle), or to automatically program thepumping subsystem 153 to pump at a pre-determined time along the heart'sECG waveform 414, as needed to properly fill the heart according towhether the heart is being perfused in retrograde or normal mode. Thesepumping adjustments may be made by use of the various graphical framesof the operator interface 146. By way of example, in response to aoperator selecting the ECG graphic frame option 492 located in thedisplay field 484 of the display screen 401, the operator interface 146displays the dialog 568 of FIG. 17F. The dialog 568 shows a graphicalrepresentation 572 of the ECG 414 along with a cursor 570. The positionof the cursor 570 indicates the point at which the pumping subsystem 153will initiate an output pumping stroke (i.e., the portion of the pumpingcycle at which the pump motor 106 will push perfusion fluid 108 to theheart 102) relative to the ECG 414 of the heart 102. By rotating amechanical knob 626 (shown in FIGS. 18A and 18B) on the operatorinterface 146, the operator moves the position of the cursor 570 toadjust when the pumping subsystem 153 will initiate the output pumpingstroke relative to the r-wave pulse 380. As described above with regardto FIGS. 15 and 16 , the pumping subsystem 153 receives an r-wave signal380 from the ECG sensors 142 and 144. The pumping subsystem 153 uses ther-wave signal 380 along with the pumping adjustment information from thecursor 570 to synchronize perfusion fluid pumping with the beating ofthe heart 102. In another example, in response to the operator pressingthe pump adjust button 625, the operator interface 146 displays thedialog 574 of FIG. 17G. From the dialog 574, the operator can select thepointer 576 and rotate the knob 626 to turn the pump motor 106 on andoff. Additionally, the operator can select the bar graphic 578 androtate the knob 626 to adjust the volume of fluid being pumped, which isdisplayed in liters/minute.

The operator interface 146 also provides a plurality of warning/remindermessages. By way of example, in FIG. 17H, the operator interface 146displays a message to remind the operator to connect to AC power torecharge the batteries. This message appears, for example, in responseto the controller 150 detecting an impending low battery condition. Theoperator interface 146 displays the message of FIG. 17I to confirm thatthe user wishes to enter standby mode and to remind the operator toinsert a portable memory device, such as magnetic or optical disk, aportable disk drive, a flash memory card or other suitable memorydevice, to download and store information regarding a particular use ofthe system 100. The operator interface 146 displays the error messages,such as the error message of FIG. 17J, in response to an identifiablefault occurring. The error messages of FIG. 17J include, for example,error information 580 to aid a service technician in diagnosing and/orrepairing the fault.

Having described an illustrative control systems and methods forachieving operation of the system 100, illustrative mechanical featuresof the system 100 will now be discussed, along with an illustrativedivision of components between the single use disposable module 634 andmultiple use module 650 units. More particularly, FIGS. 18A-18B show amechanical implementation 600 of the system of FIG. 1 , according to anillustrative embodiment of the invention. As shown, the illustrativeimplementation 600 includes a housing 602 and a cart 604. The housing602 conceptually divides into upper 602 a and lower 602 b housingsections, and includes front 606 a, rear 606 b, left 606 c, and right606 d sides. The cart 604 includes a platform 608 and wheels 610 a-610 dfor transporting the system 600 from place to place. A latch 603 securesthe housing 602 to the cart 604. To further aid in portability, thesystem 600 also includes a handle 610 hinge mounted to the upper section602 a of the left side 606 c of the housing 602, along with two rigidlymounted handles 612 a and 612 b mounted on the lower section 602 b ofthe left 606 c and right 606 d sides of the housing 602.

The housing 602 further includes a removable top 614, and a front panel615 having an upper panel 613, and a mid panel 616 hinged to a lowerpanel 617 by hinges 616 a and 616 b. The top 614 includes handles 614 aand 614 b for aiding with removal. In the illustrated embodiment, theupper panel 613 is screwed, bolted or otherwise adjoined to the top 614,such that removal of the top 614 also removes panel 613.

As shown in FIG. 18A, the system 600 includes an AC power cable 618,along with a frame 620 for securing the power cable 618, both located onthe lower section 602 b of the left side 606 c of the housing 602. Asoftware reset switch 622, also located on the lower section 602 b ofthe left side 602 c, enables an operator to restart the system softwareand electronics.

As shown in FIGS. 18A and 18B, the implementation 600 also includes theoperator interface module 146, along with a cradle 623 for holding theoperator interface module 146. The operator interface module 146includes a display 624 for displaying information to an operator, forexample, by way of the display screens of FIGS. 17A-17J. As mentionedabove, the operator interface module 146 also includes a rotatable anddepressible knob 626 for selecting between the various parameters anddisplay screens of FIGS. 17A-17J. The knob 626 may also be used to setparameters for automatic control of the system 100, as well as toprovide manual control over the operation of the system 100. Forexample, the knob 626 may be used to provide instructions to thecontroller 150 to increase perfusion fluid flow rates, gas flow rates,etc. As also discussed above with regard to FIGS. 1, 14 and 17A-17J, theoperator interface module 146 includes its own battery 368 and may beremoved from the cradle 623 and used in a wireless mode. While in thecradle 623, power connections enable the operator interface module 146to be charged. As shown, the operator interface module also includescontrol buttons 625 for controlling the pump, silencing or disablingalarms, entering or exiting standby mode, entering or adjusting ECGsynchronization mode, and starting the perfusion clock, which initiatesthe display of data obtained during organ care.

As shown in FIG. 18B, the illustrative implementation 600 also includesa battery compartment 628 and an oxygen tank bay 630, both located onthe lower section 602 b of the right side 606 d of the housing 602. Asshown, the battery compartment 628 houses the three system batteries 352a-352 c, described above with regard to FIG. 14 . According to onefeature, the battery compartment 626 includes three battery locks 632a-632 c. As described above with respect to FIG. 14 , the battery locks632 a-632 c interoperate mechanically so that only one of the threebatteries 352 a-352 c may be removed at any given time.

The disposable module 634 and the multiple use unit 650 are constructedof material that is durable yet light-weight. In some illustrativeembodiments, polycarbonate plastic is used to form one or more of thecomponents of the units 634 and 650. To further reduce the weight, thechassis 635 and the multiple use module chassis 602 are formed from lowweight materials such as, for example, carbon fiber epoxy composites,polycarbonate ABS-plastic blend, glass reinforced nylon, acetal,straight ABS, aluminum or magnesium. According to one illustrativeembodiment, the weight of the entire system 600 is less than about 85pounds, including the multiple use module, heart, batteries, gas tank,and priming, nutritional, preservative and perfusion fluids, and lessthan about 50 pounds, excluding such items. According to anotherillustrative embodiment, the weight of the disposable module 634 is lessthan about 12 pounds, excluding any solutions. According to a furtherillustrative embodiment, the multiple use module 650, excluding allfluids, batteries 352 a-352 c and oxygen supply 172, weighs less thanabout 50 pounds.

With continued reference to FIGS. 19A-19C, various views are shown ofthe implementation 600 of FIGS. 18A and 18B with the top 614 and upperfront panel 613 removed and the front mid panel 616 open, according toan illustrative embodiment of the invention. With reference to FIGS.19A-19C, the system 100 is structured as a single use disposable module634 (shown and described in detail below with reference to FIGS.24A-25C) and a multiple use module 650 (shown without the single usemodule in FIG. 20 ). As discussed in further detail below, according toone feature of the illustrative embodiment, all of the blood contactingcomponents of the system 100 are included in the single use disposablemodule 634 so that after a use, the entire single use module 634 may bediscarded, a new module 634 installed, and the system 100 available foruse again within a very brief amount of time.

According to the illustrative embodiment, the single use module 634includes a chassis 635 for supporting all of the components of thesingle use module 634. As described in more detail with regard to FIGS.24A-25C, the components of the single use module 634 include the organchamber assembly 104, described above in detail with respect to FIGS.5A-5F, the perfusion fluid reservoir 160, the oxygenator 114, theperfusion fluid pump interface 300, and all of the various fluid flowconduits and peripheral monitoring components 633.

As shown in FIGS. 19A-20A, with the top 614 removed and the front panel616 open, an operator has easy access to many of the components of thedisposable 634 and multiple use 650 modules. For example, the operatormay install, remove and view the levels of the nutrient 116 andpreservative 118 supplies of the nutritional subsystem 115. The operatormay also control operation of the nutrient 116 and preservative 118infusion pump 182. The operator may also cannulate an organ, such as theheart 102, into the organ chamber assembly 104. As described in detailbelow with reference to FIGS. 21A-21C, this configuration also providesthe operator with sufficient access to install and/or remove the singleuse module 634 to/from the multiple use module 650.

FIG. 20A shows a front perspective view of the multiple use module 650with the single use module 634 removed. As shown, the multiple usemodule 650 includes: the cart 604; the lower section 602 b of thehousing 602, along with all of the components externally mounted to it,along with those contained therein (described in further detail below,with reference to FIGS. 21A-21C and 23A-23C); the upper section 602 a ofthe housing 602 and all of the components externally mounted to it,including the top cover 614, the handles 610, 612 a, and 612 b, and thefront panel 616; the operator interface module 146; and the perfusionfluid pump motor assembly 106. As described in detail below withreference to FIGS. 21A-21C, the multiple use module 650 also includes abracket assembly 638 for receiving and locking into place the single usemodule 534.

As shown in FIG. 20A and described in further detail below withreference to FIGS. 22A-22C, the multiple use module 650 also includes afront-end interface circuit board 636 for interfacing with a front-endcircuit board (shown in FIG. 24D at 637) of the disposable module 634.As also described in detail with reference to FIGS. 22A-22C, power anddrive signal connections between the multiple use module 650 and thedisposable module 634 are made by way of corresponding electromechanicalconnectors 640 and 647 on the front end interface circuit board 636 andthe front end circuit board 637, respectively. By way of example, thefront-end circuit board 637 receives power for the disposable module 634from the front-end interface circuit board 636 via the electromechanicalconnectors 640 and 647. The front end circuit board 637 also receivesdrive signals for various components (e.g., the heater assembly 110, andthe oxygenator 114) from the controller 150 via the front-end interfacecircuit board 636 and the electromechanical connectors 640 and 647. Thefront-end circuit board 637 and the front-end interface circuit board636 exchange control and data signals (e.g., between the controller 150and the disposable module 134) by way of optical connectors (shown inFIG. 22B at 648). As described in more detail with reference to FIGS.22A-22F, the connector configuration employed between the front-end 637and front-end interface 636 circuit boards ensures that critical powerand data interconnections between the single and multiple use modules634 and 650, respectively, continue to operate even during transportover rough terrain, such as may be experienced during organ transport.

As shown in FIG. 20A, according to another feature, the upper section602 a of the housing 602 includes a fluid tight basin 652, which isconfigured to capture any perfusion fluid 108 and/or nutritional 116and/or preservative 118 solution that may inadvertently leak. The basin652 also prevents any leaked fluid 108 or solution 116/118 from passinginto the lower section 602 b of the housing 602. In this way, the basin652 shields the electronic components of the system 100 from any suchleaked fluid 108 or solution 116/118. Shielded components include, forexample, the power board 720 shown in and discussed in further detailbelow with reference to FIGS. 23C and 23D. The basin 652 includes asection 658, which extends over and shields the perfusion fluid pump 106from any inadvertently leaked fluid. According to another feature, thebasin 652 is sized to accommodate the entire volume of perfusion fluid108 (including the maintenance solutions 116/118) contained within thesystem 100 at any particular time.

Referring also to FIG. 20B, according to a further feature of theillustrative embodiment, an outer side 659 of the pump covering portion658 of the basin 652 includes a slot 660. As described in further detailbelow with reference to FIGS. 21A-21C and 24A, the slot 660 engages witha projection 662 on the single use module 634 during installation of thesingle use module 634 into the multiple use module 650.

Turning now to the installation of the single use module 634 into themultiple use module 650, FIG. 21A shows a detailed view of theabove-mentioned bracket assembly 638 located on the multiple use module650 for receiving and locking into place the single use module 634. FIG.21B shows a side perspective view of the single use module 634 beinginstalled onto the bracket assembly 638 and into the multiple use module650, and FIG. 21C shows a side view of the single use module 634installed within the multiple use module 650. With reference to FIGS.21A and 21B, the bracket assembly 638 includes two mounting brackets 642a and 642 b, which mount to an internal side of a back panel 654 of theupper housing section 602 a via mounting holes 644 a-644 d and 646 a-646d, respectively. A cross bar 641 extends between and rotatably attachesto the mounting brackets 642 a and 642 b. Locking arms 643 and 645 arespaced apart along and radially extend from the cross bar 641. Eachlocking arm 643 and 645 includes a respective downward extending lockingprojection 643 a and 645 b. A lever 639 attaches to and extends radiallyupward from the cross bar 641. Actuating the lever 639 in the directionof the arrow 651 rotates the locking arms 643 and 645 toward the back606 b of the housing 602. Actuating the lever 639 in the direction ofthe arrow 653 rotates the locking arms 643 and 645 toward the front 606a of the housing 602.

As described above with respect to FIG. 10 , the perfusion pumpinterface assembly 300 includes four projecting heat staking points 321a-321 d. As shown in FIG. 24A, during assembly, the projections 321a-321 d are aligned with corresponding apertures 657 a-657 d and heatstaked through the apertures 657 a-657 d into the projections 321 a-321d to rigidly mount the outer side 304 of the pump interface assembly 300onto the C-shaped bracket 656 of the single use module chassis 635.

With reference to FIGS. 10, 20B, 21A, 21B and 24A, during installation,in a first step, the single use module 634 is lowered into the multipleuse module 650 while tilting the single use module 634 forward (shown inFIG. 21B). This process slides the projection 662 of FIG. 24A into theslot 660 of FIG. 20B. As shown in FIG. 10 , it also positions the flange328 of the pump interface assembly 300 within the docking port 342 ofthe perfusion pump assembly 106, and the tapered projections 323 a and323 b of the pump interface assembly 300 on the clockwise side ofcorresponding ones of the features 344 a and 344 b of the pump assemblybracket 346. In a second step, the single use module 634 is rotatedbackwards until locking arm cradles 672 and 674 of the single use modulechassis 635 engage projections 643 and 645 of spring-loaded locking arm638, forcing the projections 643 and 645 to rotate upward (direction651), until locking projections 643 a and 645 a clear the height of thelocking arm cradles 672 and 674, at which point the springs cause thelocking arm 638 to rotate downward (direction 653), allowing lockingprojections 643 a and 645 a to releasably lock with locking arm cradles672 and 674 of the disposable module chassis 635. This motion causes thecurved surface of 668 of the disposable module chassis projection 662 ofFIG. 24A to rotate and engage with a flat side 670 of the basin slot 660of FIG. 20B. Lever 639 can be used to rotate the locking arm 638 upwards(direction 651) to release the single use module 635.

As shown in FIG. 10 , this motion also causes the pump interfaceassembly 300 to rotate in a counterclockwise direction relative to thepump assembly 106 to slide the flange 328 into the slot 332 of thedocking port 342, and at the same time, to slide the tapered projections323 a and 323 b under the respective bracket features 344 a and 344 b.As the tapered projections 323 a and 323 b slide under the respectivebracket features 344 a and 344 b, the inner surfaces of the bracketfeatures 344 a and 344 b engage with the tapered outer surfaces of thetapered projections 323 a and 323 b to draw the inner side 306 of thepump interface assembly 300 toward the pump driver 334 to form the fluidtight seal between the pump interface assembly 300 and the pump assembly106. The lever 639 may lock in place to hold the disposable module 634securely within the multiple use module 650.

As mentioned briefly above with reference to FIG. 20A, interlocking thesingle use module 374 into the multiple use module 650 forms bothelectrical and optical interconnections between the front end interfacecircuit board 636 on the multiple use module 650 and the front endcircuit board 637 on the single use module 634. The electrical andoptical connections enable the multiple use module 650 to power, controland collect information from the single module 634. FIG. 22A is aconceptual drawing showing various optical couplers andelectromechanical connectors on the front end circuit board 637 of thesingle-use disposable module 634 used to communicate with correspondingoptical couplers and electromechanical connectors on the front endinterface circuit board 636 of the multiple use module 650. Since thiscorrespondence is one for one, the various optical couplers andelectromechanical connectors are described only with reference to thefront end circuit board 637, rather than also depicting the front endcircuit board 650.

According to the illustrative embodiment, the front end circuit board637 receives signals from the front end interface circuit board 636 viaboth optical couplers and electromechanical connectors. For example, thefront end circuit board 637 receives power 358 (also shown in FIG. 14 )from the front end interface circuit board 636 via the electromechanicalconnectors 712 and 714. The front end circuit board 637 the power to thecomponents of the single use module 634, such as the various sensors andtransducers of the single use module 634. Optionally, the front endcircuit board 637 converts the power to suitable levels prior todistribution. The front end interface circuit board 636 also providesthe heater drive signals 281 a and 281 b of FIG. 13 to the applicableconnections 282 a on the heater 246 of FIG. 6E via the electromechanicalconnectors 704 and 706. Similarly, the electromechanical connectors 708and 710 couple the heater drive signals 283 a and 283 b of FIG. 13 tothe applicable connections in 282 b of the heater 248. The front-endcircuit board 637 may receive a defibrillation command from the frontend interface circuit board 636 via the electromechanical connector 687.In response, the front end circuit board 637 generates thedefibrillation signal 143 having suitable current and voltage levels,and as shown in FIG. 5E, couples the signal 143 to the organ chamberassembly 104 via the electrical interface connections 235 a-235 b.

In another illustrative embodiment, the defibrillation command can beprovided from an external source (not shown), rather than through thecircuit board 636. As an example, and with reference to FIG. 5E and FIG.1 , an external defibrillation device can be plugged into the electricalcoupler 613 shown in FIG. 24E, which is connected to the electricalinterface connections 235 a-235 b. The external defibrillation devicesends a defibrillation signal 143 through the coupler 613 and theinterface connections 235 a and 235 b to electrodes 142 and 144. Theelectrodes 142 and 144 then deliver the signal 143 to the heart 102.This alternative embodiment allows the user to provide defibrillation(and pacing) without passing the signal 143 through the circuit boards618, 636, and 637. An exemplary external defibrillation device mayinclude the Zoll M-Series Portable Defibrillator.

According to the illustrative embodiment, the front end circuit board637 receives signals from temperature, pressure, fluid flow-rate,oxygentation/hematocrit and ECG sensors, amplifies the signals, convertsthe signals to a digital format and provides them to the front-endinterface circuit board 636 by way of optical couplers. For example, thefront end circuit board 637 provides the temperature signal 121 from thesensor 120 on the heater plate 250 (shown in FIGS. 6A and 13 ) to thefront end interface circuit board 636 by way of the optical coupler 676.Similarly, the front end circuit board 637 provides the temperaturesignal 123 from the sensor 122 on the heater plate 252 (shown in FIGS.6A and 13 ) to the front end interface circuit board 636 by way of theoptical coupler 678. The front end-circuit board 637 also provides theperfusion fluid temperature signals 125 and 127 from the thermistorsensor 124 (shown in FIGS. 6A and 13 ) to the front end interfacecircuit board 636 via respective optical couplers 680 and 682. Perfusionfluid pressure signals 129, 131 and 133 are provided from respectivepressure transducers 126, 128 and 130 to the front end interface circuitboard 636 via respective optical couplers 688, 690 and 692. The frontend circuit board 637 also provides perfusion fluid flow rate signals135, 137 and 139 from respective flow rate sensors 134, 136 and 138 tothe front end interface circuit board 636 by way of respective opticalcouplers 694, 696 and 698. Additionally, the front end circuit board 637provides the oxygen saturation 141 and hematocrit 145 signals from theoxygen saturation sensor 140 to the front end interface circuit board636 by way of respective optical couplers 700 and 702.

In other illustrative embodiments, one or more of the foregoing sensorsare wired directly to the main system board 718 (described below withreference to FIG. 23D) for processing and analysis, thus by-passing thefront-end interface board 636 and front-end board 637 altogether. Suchembodiments may be desirable where the user prefers to re-use one ormore of the sensors prior to disposal. In one such example, the flowrate sensors 134, 136 and 138 and the oxygen and hematocrit sensor 140are electrically coupled directly to the system main board 718 throughelectrical coupler 611 shown in FIG. 23C, thus by-passing any connectionwith the circuit boards 636 and 637.

As described above with respect to FIGS. 11-16 , the controller 150employs the signals provided to the front end interface circuit board636, along with other signals, to transmit data and otherwise controloperation of the system 100. As described with respect to FIGS. 17A-17J,the controller 150 also displays sensor information, and may display tothe operator various alarms relating to the sensor information by way ofthe operator interface module 146.

FIG. 22B illustrates the operation of an exemplary electromechanicalconnector pair of the type employed for the electrical interconnectionsbetween the circuit boards 636 and 637. Similarly, FIG. 22C illustratesthe operation of an optical coupler pair of the type employed for theoptically coupled interconnections between the circuit boards 636 and637. One advantage of both the electrical connectors and opticalcouplers employed is that they ensure connection integrity, even whenthe system 100 is being transported over rough terrain, for example,such as being wheeled along a tarmac at an airport, being transported inan aircraft during bad weather conditions, or being transported in anambulance over rough roadways. Additionally, the optical couplerselectrically isolate the temperature, pressure and ECG sensors from therest of the system 100, which prevents a defibrillation signal fromdamaging the system 100. The power for the front end board 637 isisolated in a DC power supply located on the front end interface board636.

As shown in FIG. 22B, the electromechanical connectors, such as theconnector 704, include a portion, such as the portion 703, located onthe front end interface circuit board 636 and a portion, such as theportion 705, located on the front end circuit board 637. The portion 703includes an enlarged head 703 a mounted on a substantially straight andrigid stem 703 b. The head 703 includes an outwardly facingsubstantially flat surface 708. The portion 705 includes a substantiallystraight and rigid pin 705 including an end 705 a for contacting thesurface 708 and a spring-loaded end 705 b. Pin 705 can move axially inand out as shown by the directional arrow 721 while still maintainingelectrical contact with the surface 708 of the enlarged head 703 a. Thisfeature enables the single use module 634 to maintain electrical contactwith the multiple use module 650 even when experiencing mechanicaldisturbances associated with transport over rough terrain. An advantageof the flat surface 708 is that it allows for easy cleaning of theinterior surface of the multiple use module 650. According to theillustrative embodiment, the system 100 employs a connector for theelectrical interconnection between the single use disposable 634 andmultiple use 650 modules. An exemplary connector is part no. 101342 madeby Interconnect Devices. However, any suitable connector may be used.

Optical couplers, such as the optical couplers 684 and 687 of the frontend circuit board 637, are used and include corresponding counterparts,such as the optical couplers 683 and 685 of the front end interfacecircuit board 636. The optical transmitters and optical receiverportions of the optical couplers may be located on either circuit board636 or 637. For example, in the case of the ECG signal 379, the opticaltransmitter 684 is located on the circuit board 637 for receiving theelectrical signal 379 and optically coupling it to the optical receiver683 on the circuit board 636. In the case where the defibrillator signalis transmitted through the circuit boards 636 and 637 (rather thandirectly to the main board 718), the optical transmitter 685 on thecircuit board 636 optically couples the signal to the optical receiver687 on the circuit board 637.

As in the case of the electromechanical connectors employed, allowabletolerance in the optical alignment between the optical transmitters andcorresponding optical receivers enables the circuit boards 636 and 637to remain in optical communication even during transport over roughterrain. According to the illustrative embodiment, the system 100 usesoptical couplers made under part nos. 5FH485P and/or 5FH203PFA by Osram.However, any suitable coupler may be used.

The couplers and connectors facilitate the transmission of data withinthe system 100. The front-end interface circuit board 636 and thefront-end board 637 transmit data pertaining to the system 100 in apaced fashion. As shown in FIG. 22C, circuit board 636 transmits to thefront-end board 637 a clock signal that is synchronized to the clock onthe controller 150. The front-end circuit board 637 receives this clocksignal and uses it to synchronize its transmission of system data (suchas temperatures, pressures, ECG, r-wave detection, or other desiredinformation) with the clock cycle of the controller 150. This data isdigitized by a processor on the front-end circuit board 637 according tothe clock signal and a pre-set sequence of data type and source address(i.e. type and location of the sensor providing the data). The front-endinterface circuit board 636 receives the data from the front-end board637 and transmits the data set to the main board 618 for use by thecontroller 150 in evaluation, display, and system control, as describedabove with reference to FIGS. 11, 12 and 14 . Additional opticalcouplers can be added between the multiple use module and single usemodule for transmission of control data from the multiple use module tothe single use module, such data including heater control signals orpump control signals.

Having described the mechanical, electrical and optical interconnectionsbetween the single use module 634 and the multiple use module 650,additional components of the multiple use module 650 will now bediscussed with respect to FIGS. 23A-23D, followed by a description ofthe mechanical arrangement of the components of the single use module634 with respect to FIGS. 24A-28C. As shown in FIGS. 23A-23D, with thewalls of the housing 602 removed, in addition to those componentspreviously discussed, the multiple use module 650 includes an onboardgas supply 172, located in the lower section 602 b of the housing 602.The gas supply 172 is depicted in FIGS. 23A-23D as a tank, positionedwithin the gas tank bay 630 by a support structure 712, which abuts thetank 172. Optionally, the gas supply 172 may be further secured withinthe gas tank bay 630 by a strap and buckle assembly 714 or othersuitable mechanism. With particular reference to FIG. 23B and asdescribed above with reference to FIG. 1 , the gas supply 172 providesgas to the system 100 through the gas regulator 174 and the gas flowchamber 176. The gas pressure sensor 132 measures the gas pressure inthe gas supply 172, and the gas pressure gauge 178 provides a visualindication of the fullness of the gas supply 172. Additionally, anelectrical connection between the controller 150 and the gas flowchamber 176 enables the controller 150 to regulate automatically the gasflow into the oxygenator 114.

As shown most clearly in FIG. 23C, the battery bay 628 houses thebatteries 352 a-352 c. As noted above with reference to FIG. 14 , alock-out mechanism is used to prevent more than one of the batteries 352a-352 c from being removed from the battery bay 628 at a given timewhile the system 100 is operating.

As discussed above, the system 100 includes a plurality ofinterconnected circuit boards for facilitating power distribution anddata transmission to, from and within the system 100. Particularly, asdiscussed above with reference to FIGS. 22A-22E and as shown in FIG.23C, the multiple use module 650 includes a front end interface circuitboard 636, which optically and electromechanically couples to the frontend circuit board 637 of the single use module 650. As also shown inFIG. 23C, the system 100 further includes a main board 718, a powercircuit board 720, and a battery interface board 711 located on themultiple use module 650. The main board 718 is configured to allow thesystem 100 to be fault tolerant, in that if a fault arises in theoperation of a given circuit board (as shown in FIG. 23D), the mainboard 718 saves pumping and heating parameters in non-volatile memory.When the system 100 reboots, it can re-capture and continue to performaccording to such parameters.

Referring to the conceptual drawing of FIG. 23D, cabling 731 bringspower (such as AC power 351) from a power source 350 to the powercircuit board 720 by way of connectors 744 and 730. The power supply 350converts the AC power to DC power and distributes the DC power asdescribed above with reference to the power subsystem of FIG. 14 .Referring also to FIGS. 14 and 22A, the power circuit board 720 couplesDC power and a data signal 358 via respective cables 727 and 729 fromthe connectors 726 and 728 to corresponding connectors 713 and 715 onthe front end interface circuit board 636. Cable 729 carries both powerand a data signal to the front end interface board 636. Cable 727carries power to the heater 110 via the front-end interface board 636.The connectors 713 and 715 interfit with corresponding connectors 712and 714 (described above with respect to FIG. 22A) on the front endcircuit board 637 on the single use module 634 to provide power to thesingle use module 634.

As shown in FIG. 23D, the power circuit board 720 also provides DC power358 and a data signal from the connectors 732 and 734, respectively, onthe power circuit board 720 to corresponding connectors 736 and 738 onthe main circuit board 718 by way of the cables 733 and 735. Referringalso to FIGS. 14 and 19A, the cable 737 couples DC power 358 and a datasignal from a connector 740 on the main circuit board 718 to theoperator interface module 146 by way of a connector 742 on the operatorinterface module cradle 623. The power circuit board 720 also providesDC power 358 and a data signal from connectors 745 and 747 via cables741 and 743 to connectors 749 and 751 on a battery interface board 711.Cable 741 carries the DC power signal and cable 743 carries the datasignal. Battery interface board 711 distributes DC power and data tobatteries 352 a, 352 b and 352 c. Batteries 352 a, 352 b and 352 ccontain electronic circuits that allow them to communicate with eachother to monitor the respective charges, as described above in-referenceto FIG. 14 , so that the controller 150 can monitor and control thecharging and discharging of the batteries 352 a-352 c.

According to some illustrative embodiments, the controller 150 islocated on the main circuit board 718 and performs all control andprocessing required by the system 100. However, in other illustrativeembodiments, the controller 150 is distributed, locating some processingfunctionality on the front end interface circuit board 636, some on thepower circuit board 720, and/or some in the operator interface module146. Suitable cabling is provided between the various circuit boards,depending on whether and the degree to which the controller 150 isdistributed within the system 100.

As described above with reference to FIGS. 19A-19C and 23A-23C, thesystem 100 mechanically divides into the single use disposable module634 and the multiple use module 650. As also described above, accordingto the illustrative embodiment, the single use module 634 includes allor substantially all of the perfusion fluid 108 contactingelements/assemblies of the system 100, along with various peripheralcomponents, flow conduits, sensors and support electronics for operatingthe blood contacting components. As discussed above with reference toFIGS. 22A and 23D, according to the illustrative embodiment, the module634 does not include a processor, instead relying on the controller 150,which may, for example, be distributed between the front end interfacecircuit board 636, the power circuit board 720, the operator interfacemodule 146, and the main circuit board 718, for control. However, inother illustrative embodiments, the single use module 634 may includeits own controller/processor, for example, on the front end circuitboard 637.

Referring to FIGS. 24A-28C, the single use module 634 will next bedescribed in terms of the components included therein. After that,exemplary forward and retrograde flow modes are traced through thedescribed components.

Referring first to FIG. 24A, the disposable module 634 includes achassis 635 having upper 750 a and lower 750 b sections. The uppersection 750 a includes a platform 752 for supporting various components.The lower section 750 b supports the platform 752 and includesstructures for pivotably connecting with the multiple use module 650.More particularly, the lower chassis section 750 b includes the C-shapedmount 656 for rigidly mounting the perfusion fluid pump interfaceassembly 300, and the projection 662 for sliding into and snap fittingwith the slot 660 of FIG. 20B. The lower chassis section 750 b alsoprovides structures for mounting the oxygenator 114. As shown in FIGS.25A and 25C, the lower section 750 b further includes structures formounting the heater assembly 110. Additionally, the reservoir 160 mountsto the underside of the platform 725 and extends into the lower chassissection 750 b. Various sensors, such as the O2 saturation and hematocritsensor 140 (shown in FIG. 24A and described in detail below withreference to FIGS. 28A-28C), the flow rate sensor 136 (shown in FIG.24A), the flow rate sensor 138 (shown in FIG. 25B), are located withinand/or mount to the lower chassis section 750 b. The flow pressurecompliance chamber 188 (shown in FIG. 25B) is also located in the lowerchassis section 750 b. As shown in FIG. 24D, the lower chassis section750 b also mounts the front end circuit board 637. Conduits located inthe lower chassis section 750 b are described in further detail belowwith reference to the normal and retrograde flow paths through thesingle use module 634.

Referring to FIGS. 24A-25C, and as mentioned above, the upper chassissection 750 a includes the platform 752. The platform 752 includeshandles 752 a and 752 b formed therein to assist in installing andremoving the single use module 634 from the multiple use module 650.Alternatively, such handles can be located on the platform 757 to allowfor easier accessibility during installation of the single use moduleinto the multiple use module. As shown most clearly in FIG. 24C, anangled platform 757 mounts onto the platform 752. The organ chamberassembly 104 mounts to the angled platform 757. According to theillustrative embodiment, with the single use module 634 installed withinthe multiple use module 650, the platform 757 is angled at about10.degree. to about 80.degree. relative to horizontal, to provide anoptimal angle of operation for the heart 102 when placed within theorgan chamber assembly 104. In some illustrative embodiments, theplatform 757 is angled at about 20.degree. to about 60.degree., or about30.degree. to about 50.degree. relative to horizontal. The flow modeselector valve 112, the flow rate sensor 134, and the perfusion fluidflow pressure compliance chambers 184 and 186 also mount onto the angledplatform 757.

Referring to FIG. 24E, several fluid ports mount to the platform 752.For example, a fluid sampling port 754 enables an operator to sample theflow into and/or out of the aorta 158 via the cannulation interface 162on the organ chamber assembly 104. A fluid sampling port 755 enables theoperator to sample the flow into the left atrium 152 via the interface170 on the organ chamber assembly 104. Additionally, a fluid port 758enables the operator to sample the coronary flow out of the pulmonaryartery 164 via the pulmonary artery interface 166 on the organ chamber104. According to the illustrative embodiment, the operator turns the arespective valve 754 a, 755 a or 758 a to obtain flow from the samplingports 754, 755 and 758. Flow from the particular port selected isprovided at a single common outlet 764. According to one feature, onlyflow from the left most port selected is provided at the outlet 764. Byway of example, if the operator opens both ports 755 and 758, only flowfrom port 755 is provided at the outlet 764. In this way, system 100reduces the likelihood of an operator mixing samples from multipleports.

The single use module 634 also includes a general injection port 762,operable with the valve 762 a, for enabling the operator to injectmedication into the perfusion fluid 108, for example, via the reservoir160. Both the sampling 764 and injection 762 ports mount to the platform752. Also located on the upper chassis section 750 a is an infusion port766, operable with the valve 766 a, for flowing the nutritional 116 andpreservative 118 fluids into the perfusion fluid 108. The upper chassissection 750 a also includes a tube 774 for loading the exsanguinatedblood from the donor into the reservoir 160. As shown in FIG. 24D, thesingle use module 634 also includes non-vented caps 776 for replacingvented caps on selected fluid ports that are used while running asterilization gas through the single use module 634 duringsterilization. Preferably, such sterilization takes place prior topackaging the single use module 634 for sale.

The upper chassis section 750 a also includes the flow clamp 190 forregulating back pressure applied to the left atrium 152 when the heart102 is cannulated and operating in normal flow mode in the organ chamberassembly 104. The upper chassis section 750 a further includes a tricklevalve 768. The trickle valve 768 may be opened and closed with thehandle 768 a to regulate a small fluid flow to the left atrium 152 tomoisten the left atrium 152 during retrograde flow mode. The upperchassis section 750 a also includes ports 770 for infusion of additionalsolutions and 772 for purging the oxygenator 114, operable withrespective valves 770 a and 772 a.

As shown most clearly in FIGS. 24A and 24D, the upper chassis section750 further includes the flow pressure probes 126, 128 and 130. Asdescribed above with reference to FIG. 1 , the probe 126 measures thepressure of the perfusion fluid 108 flowing into/out of the aorta 158.The probe 128 measures the pressure of the perfusion fluid 108 flowinginto the left atrium 152 through the pulmonary vein 168. The probe 130measures the pressure of the perfusion fluid 108 flowing out of thepulmonary artery 164. Each probe includes a respective connector 126 a,128 a and 130 a (shown shortened for clarity) for coupling a respectivesignal 129, 131, and 133 to the front end circuit board 637.

Referring particularly to the single use module 654 cross-sectional sideview of FIG. 24C, the reservoir 160 includes several components. Morespecifically, the reservoir 160 includes four inlets: 782, 784, 786 and788. The inlet 782 transfers perfusion fluid 108 from the drain 201 ofthe organ chamber 194 into the reservoir 160. The inlet 784 receivesexsanguinated blood from the tube 774. The inlet 786 receives oxygenatedperfusion fluid 108 from the oxygenator 114, and the inlet 788 receivesperfusion fluid 108 out of the aorta 158 via the back pressure clamp190. The reservoir 160 also has an outlet 790, which provides theperfusion fluid to the one way inlet valve 191. The reservoir 160further includes a defoamer 778 and a filter 780. The defoamer 778removes bubbles out of the perfusion fluid 108 as it enters thereservoir 160. According to the illustrative embodiment, the defoamer ismade of porous polyurethane foam with an antifoam coating. The filter780 is a polyester felt, which filters debris, blood particles, emboli,and air bubbles out of the perfusion fluid as it enters the reservoir160.

As mentioned above in the summary, the O.sub.2 saturation and hematocritsensor 140 employed in the single use module 634 includes importantadvantages over prior art approaches. FIGS. 28A-28C depict anillustrative embodiment of the O.sub.2 saturation and hematocrit sensor140 of the invention. As shown in FIG. 28A, the sensor 140 includes anin-line cuvette shaped section of tube 812 connected to the conduit 798,which has at least one optically clear window through which an infraredsensor can provide infrared light. Exemplary sensors used in the in-linecuvette-shaped tube 812 are those made by Datamed, BL0P4. As shown inthe cross-sectional view of FIG. 28B, the cuvette 812 is a one-piecemolded part having connectors 801 a and 801 b. The connectors 801 a and801 b are configured to adjoin to connecting receptacles 803 a and 803b, respectively, of conduit ends 798 a and 798 b. This interconnectionbetween cuvette 812 and conduit ends 798 a and 798 b is configured so asto provide a substantially constant cross-sectional flow area insideconduit 798 and cuvette 812. The configuration thereby reduces, and insome embodiments substantially removes, discontinuities at theinterfaces 814 a and 814 b between the cuvette 812 and the conduit 798.Reduction/removal of the discontinuities enables the blood basedperfusion fluid 108 to flow through the cuvette with reduced lysing ofred blood cells and reduced turbulence, which enables a more accuratereading of perfusion fluid oxygen levels. This also reduces damage tothe perfusion fluid 108 by the system 100, which ultimately reducesdamage done to the heart 102 while being perfused by the system 100.

According to the illustrative embodiment, the cuvette 812 is formed froma light transmissive material, such as any suitable light transmissiveglass or polymer. As shown in FIG. 28A, the sensor 140 also includes anoptical transceiver 816 for directing light waves at perfusion fluid 108passing through the cuvette 812 and for measuring light transmissionand/or light reflectance to determine the amount of oxygen in theperfusion fluid 108. As illustrated in FIG. 28C, in some embodiments alight transmitter is located on one side of the cuvette 812 and adetector for measuring light transmission through the perfusion fluid108 is located on an opposite side of the cuvette 812. FIG. 28C depictsa top cross-sectional view of the cuvette 812 and the transceiver 816.The transceiver 816 fits around cuvette 812 such that transceiverinterior flat surfaces 811 and 813 mate against cuvette flat surfaces821 and 823, respectively, while the interior convex surface 815 oftransceiver 816 mates with the cuvette 812 convex surface 819. Inoperation, when uv light is transmitted from the transceiver 816, ittravels from flat surface 811 through the fluid 108 inside cuvette 812,and is received by flat surface 813. The flat surface 813 may beconfigured with a detector for measuring the light transmission throughthe fluid 108.

The fluid flow path through the single use module 634 in both normal andretrograde flow modes will now be described with reference to FIGS.24A-24D and FIG. 25A. As described above with reference to FIGS. 1-4 ,the system 100 can maintain the heart 102 in two modes of operation; anormal flow mode, shown in FIG. 3 , and a retrograde flow mode shown inFIG. 4 . As mentioned above with regard to FIG. 1 , to change betweennormal and retrograde flow modes, the system 100 provides the flow modeselector valve 112, shown in detail in FIGS. 26A and 26B. To operate innormal flow mode, the operator sets the flow mode selector valve handle112 e to the position indicated in FIG. 24A. This has the effect ofaligning the flow paths through the selector valve 112 as shown in FIG.26A. Specifically, in normal flow mode, fluid can flow into port 112 b,through the flow channel 112 f and out the port 112 c. Additionally,fluid can flow into port 112 d, through the flow channel 112 g and outthe port 112 a. To operate in retrograde flow mode, the operator setsthe flow mode selector valve handle 112 e to the position indicated inFIG. 24B. This has the effect of aligning the flow paths through theselector valve 112 as shown in FIG. 26B. Specifically, in retrogradeflow mode, fluid can flow into port 112 b, through the flow channel 112h and out the port 112 d.

Referring to FIG. 24A, in normal flow mode, the reservoir 160 providesthe perfusion fluid 108 to the one way inlet valve 191 of the perfusionpump interface assembly 300. Referring to FIG. 25A, the perfusion pump106 pumps the perfusion fluid 108 out the outlet valve 310. Referring toFIG. 25C, the perfusion fluid 108 then flows through the conduit 792 andthe compliance chamber 188 and into the inlet 110 a of the heaterassembly 110. The heater assembly 110 heats the perfusion fluid 108 andthen flows it out the heater outlet 110 b. Referring to FIG. 24A, theheated perfusion fluid 108 flows from the heater outlet 110 b in thelower chassis section 750 b through the chassis plate 752 and into theport 112 b of the mode select valve 112 via the conduit 794. Referringalso to FIG. 24D, the perfusion fluid 108 flows out the mode valve port112 c, through the compliance chamber 186, the conduit 796, and thepressure sensor 128 into the pulmonary vein cannulation interface 170 onthe organ chamber assembly 104.

Referring to FIG. 24A, in normal flow mode, the heart 102 pumps theperfusion fluid 108 out the pulmonary artery 164 through the pulmonaryartery interface 166 and the pressure sensor 130. The conduit 796 thenflows the perfusion fluid 108 from the pulmonary artery interface 166through the plate 752 and through the O.sub.2 saturation and hematocritsensor 140. Referring also to FIGS. 25A and 25C, the conduit 798 thenflows the perfusion fluid 108 from the sensor 140 through the flow-ratesensor 136 into the oxygenator 114. The conduit 800 flows the perfusionfluid 108 from the oxygenator 114 back into the reservoir 160 by way ofthe reservoir inlet 786.

Referring to FIGS. 24A, 24D and 24E, in normal flow mode, the heart 102also pumps the perfusion fluid 108 out of the aorta 158 through theaorta interface 162 and the pressure sensor 126. The conduit 802 flowsthe perfusion fluid 108 from the pressure sensor 126 through the flowrate sensor 134 and back into the port 112 d on the flow mode selectorvalve 112. A clamp 804 holds the conduit 802 in place. A conduit 806flows the perfusion fluid 108 out the port 112 a from the flow modeselector valve 112 through the compliance chamber 184 and the backpressure adjustment clamp 190. As mentioned above, the clamp 190 may beadjusted to restrict flow through the conduit 806 to adjust the backpressure seen by the aorta 158 during normal flow mode to morerealistically simulate normal physiologic conditions. The compliancechamber 184, which can expand and contract as perfusion fluid 108 ispumped into and out of it, interoperates with the clamp 190 to dampenflow pressure spikes to further improve simulation of near-normalphysiologic conditions. The after-load clamp 190 is configured toclosely emulate systemic vascular resistance of the human body whichaffects aortic pressure, left atrial pressure, and coronary flow. Aconduit 808 returns the perfusion fluid 108 into the reservoir 160 byway of the reservoir inlet 788.

In retrograde flow mode, the flow mode selector valve 112 is positionedas shown in FIG. 24B. Referring to FIG. 24B, the reservoir 160 providesthe perfusion fluid 108 to the inlet valve 191. As shown in FIG. 25A,the perfusion pump 106 pumps the perfusion fluid 108 out the outletvalve 310. As shown in FIG. 25C, the perfusion fluid 108 then flowsthrough the conduit 792 and the compliance chamber 188 and into theinlet 110 a of the heater assembly 110. The heater assembly 110 heatsthe perfusion fluid 108 and then flows it out the heater outlet 110 b.Referring to FIG. 24B, the heated perfusion fluid 108 flows from theheater outlet 110 b in the lower chassis section 750 b through thechassis plate 752 and into the input 112 b of the mode select valve 112via the conduit 794. Referring also to FIG. 24D, the perfusion fluid 108flows out the mode valve outlet 112 d, into the conduit 802, through theflow rate sensor 134, the pressure sensor 126 and into the aorta 158 viathe aorta interface 162. The perfusion fluid 108 then flows through thecoronary sinus 155 and the rest of the coronary vasculature.

Referring to FIG. 24B, in retrograde flow mode, the heart 102 pumps theperfusion fluid 108 out of the pulmonary artery 164 and through thepulmonary artery interface 166 and the pressure sensor 130. The conduit796 then flows the perfusion fluid from the pulmonary artery interface166 through the plate 752 and into the O.sub.2 saturation and hematocritsensor 140. Referring also to FIGS. 25A and 25C, the conduit 798 thenflows the perfusion fluid 108 from the sensor 140 through the flow ratesensor 136 into the oxygenator 114. The conduit 800 flows the perfusionfluid 108 from the oxygenator 114 back into the reservoir 160 by way ofthe reservoir inlet 786. In retrograde flow mode, substantially noperfusion fluid is pumped into or out of the left atrium 152 via thepulmonary vein 168 and the pulmonary vein interface 170, with theexception of a small amount of perfusion fluid diverted by the tricklevalve 768 from the conduit 794 around the flow mode selector valve 112into the compliance chamber 186. As mentioned above, the trickle flowprovides sufficient perfusion fluid 108 to keep the left atrium 152moistened during retrograde flow.

As described above, the illustrative embodiment of the system 100 hasone or more sensors or probes for measuring fluid flow and pressure. Theprobes and/or sensors may be obtained from standard commercial sources.The flow rate sensors 134, 136 and 138 are conventional, ultrasonic flowsensors, such as those available from Transonic Systems Inc., Ithaca,N.Y. The fluid pressure probes 126, 128 and 130 may be conventional,strain gauge pressure sensors available from MSI or G.E. Thermometrics.Alternatively, a pre-calibrated pressure transducer chip can be embeddedinto organ chamber connectors and wired to a data collection site suchas the front end board 637.

Having described the electrical and mechanical components andfunctionality of illustrative embodiments of the system 100 and certainmodes of operation thereof, the system 100 will next be described withreference to the illustrative organ harvest and transplant procedures ofFIGS. 29A and 29B. More particularly, FIG. 29A is a flow diagram 900depicting exemplary methodologies for harvesting the donor heart 102 andcannulating it into the system 100 at a donor location. FIG. 29B depictsparticular points of care for handling the heart 102 in preparation forcannulation, and FIG. 30 is a flow diagram 902 of exemplarymethodologies for removing the donor organ 102 from the system 100 andtransplanting it into a patient at a recipient site.

As shown in FIG. 29A, the process of obtaining and preparing the heart102 for cannulation and transport begins by providing a suitable organdonor 904. The organ donor is brought to a donor location, whereupon theprocess of receiving and preparing the donor heart 102 for cannulationand transport proceeds down two intersecting pathways 906 and 908. Thepathway 906 principally involves preparing the donor heart 102 fortransplant, while the pathway 908 principally involves preparing thesystem 100 to receive the donor heart 102 and then transporting theheart 102 via system 100 to the recipient site.

With particular reference to FIG. 29A, the first pathway 906 includesexsanguinating the donor 910, arresting the donor heart 914, explantingthe heart 916, and preparing the heart 102 for cannulation 918 into thesystem 100. In particular, in the exsanguination step 910, the donor'sblood is removed and set aside so it can be used to perfuse the heart102 during preservation on the system 100. This step is performed byinserting a catheter into either the arterial or venous vasculature ofthe donor to allow the donor's blood to flow out of the donor and becollected into a blood collection bag. The donor's blood is allowed toflow out until the necessary amount of blood is collected, typically1.0-2.5 liters, whereupon the catheter is removed. The blood extractedthrough exsanguination is then filtered and added to a fluid reservoir160 of the system 100 in preparation for use with the system 100.Alternatively, the blood can be exsanguinated from the donor andfiltered for leukocytes and platelets in a single step that uses anapparatus having a filter integrated with the cannula and bloodcollection bag. An example of such a filter is a Pall BC2B filter. Afterthe donor's blood is exsanguinated, the donor heart 102 is injected instep 914 with a cardioplegic solution to temporarily halt beating inpreparation for harvesting the heart 102.

After the heart 102 is arrested, the heart 102 is explanted 916 from thedonor and prepared 918 for loading onto the system 100. In general, thesteps of explanting the heart 916 and preparing for loading 918 involvesevering the connections between the vasculature of the heart 102 andthe interior chest cavity of the donor, suturing various of the severedconnections, then lifting the heart 102 from the chest cavity.

More particularly, as shown in FIG. 29B, the right and left pulmonaryarteries 164 a and 164 b are severed, and the right pulmonary artery 164a is tied-off by a surgical thread 901 a or other suitable mechanism.The tying prevents fluid from flowing through the severed end 903 a ofthe left pulmonary artery 164 a. As described above with reference toFIGS. 24A-24B, the left pulmonary artery 164 b remains unsutured toallow it to be cannulated to the organ chamber assembly 104, therebyallowing perfusion fluid 108 to flow through the left pulmonary artery164 b, through the pulmonary artery cannulation interface 170, and backto the reservoir 160. The left pulmonary veins 168 b and 169 b and theright pulmonary veins 168 a and 169 a are also severed, and all except asingle pulmonary vein 169 b are tied off with surgical thread 901 b, 901c, and 901 d, respectively. This prevents fluid from flowing through thesevered ends 903 b and 903 c of the right pulmonary veins 168 a and 169a, or through the severed end 903 d of the left pulmonary vein 168 b,but allows the untied pulmonary vein to be cannulated to the organchamber assembly 104 through the pulmonary vein interface 170. Asdescribed above with reference to FIGS. 24A-24B, this arrangement allowsthe perfusion fluid 108 to flow through the right pulmonary artery 164b, through the pulmonary artery interface 166, and back to theoxygenator 114. Alternatively, blood can be expelled from the rightventricle via cannulating the pulmonary arterial trunk. The pulmonaryarterial trunk is not shown but includes the segment of pulmonary artery164 between the branches 164 a and 164 b of the pulmonary artery 164 andthe right ventricle 159. The superior vena cava 161 is also severed and,once the heart is connected to the system 100 and begins beating, istied with thread 901 e to prevent fluid from flowing through its end 903e. The inferior vena cava 163 is similarly severed and tied with thread901 f or oversewn to prevent fluid from flowing through its end 903 f.The aorta 158 is also severed (in the illustrated embodiment at a pointdownstream from the coronary sinus 155) but is not tied off, allowing itto be cannulated to the organ chamber assembly 104. In one embodiment,the aorta 158 is cannulated to an aortic connector, which can be easilyattached to the aorta interface 170.

With continued reference to the flow chart of FIG. 29A, after the heartvasculature is severed and appropriately tied, the heart 102 is thenloaded onto the system 100 by inserting it into the organ chamberassembly 104 and cannulating the aorta 158, left pulmonary artery 164 b,and a pulmonary vein 169 b to the appropriate points in the organchamber assembly 104.

Often, hearts obtained from donors who have also donated their lungs aremissing part or all of the left atrium 152. In this situation, the heart102 can still be instrumented and perfused in the retrograde mode bycannulating the aorta 158 and either the right pulmonary artery 164 a orpulmonary artery trunk (not shown, but described above), and allowingany remaining left atrium 152 portion to remain open during thepreservation period.

With continued reference to FIG. 29A, during the preparation of theheart via path 906, the system 100 is prepared through the steps of path908 so it is primed and waiting to receive the heart 102 for cannulationand transport as soon as the heart 102 is prepared. By quicklytransferring the heart 102 from the donor to the system 100, andsubsequently perfusing the heart 102 with the perfusion fluid 108, amedical operator can minimize the amount of time the heart 102 isdeprived of oxygen and other nutrients, and thus reduce ischemia andother ill effects that arise during current organ care techniques. Incertain embodiments, the amount of time between infusing the heart 102with cardioplegic solution and beginning flow of the perfusion fluid 108through the heart 102 via the system 100 is less than about 15 minutes.In other illustrative embodiments, the between-time is less than about ½hour, less than about 1 hour, less than about 2 hours, or even less thanabout 3 hours. Similarly, the time between transplanting the heart intoan organ care system 100 and bringing the heart 102 to a nearphysiological temperature (e.g., between about 34.degree. C. and about37.degree. C.) occurs within a brief period of time so as to reduceischemia within the heart tissues. In some illustrative embodiments, theperiod of time is less than about 5 minutes, while in other applicationsit may be less than about ½ hour, less than about 1 hour, less thanabout 2 hours, or even less than about 3 hours. According to someillustrative embodiments, the heart can be transferred directly from thedonor to the system 100, without the use of cardioplegia, and in suchapplications the time to beginning the flow of warm perfusion fluid 108and/or time to the heart reaching near physiologic temperature issimilarly less than about 5 minutes, less than about ½ hour, less thanabout 1 hour, less than about 2 hours, or even less than about 3 hours.In one implementation, the donor heart is not arrested prior to removalfrom the donor, and is instrumented onto the system 100 while the heart102 is still beating.

As shown in FIG. 29A, the system 100 is prepared in pathway 908 througha series of steps, which include preparing the single use module 634(step 922), priming the system 100 with priming solution (step 924),filtering the blood from the donor and adding it to the system 100reservoir 160 (step 912), and connecting the heart 102 into the system100 (step 904). In particular, the step 922 of preparing the single usemodule 634 includes assembling the disposable single use module 634.Suitable assemblies are shown, for example, in FIGS. 24A-24D, FIGS.25A-25C, and FIG. 26 . After the module 634 is assembled, or provided inthe appropriate assembly, it is then inserted into multiple use module650 through the process described above with reference to FIGS. 21A-21C.

In step 924, the loaded system 100 is primed with priming solution, asdescribed in more particular detail below with reference to Table 1.According to one feature, to aid in priming, the system 100 provides anorgan bypass conduit 810 shown installed into the organ chamber assembly104 in FIG. 27A. As depicted, the bypass conduit includes three segments810 a-810 c. Segment 810 a attaches to the pulmonary artery cannulationinterface 170. The segment 810 b attaches to the aorta cannulationinterface 810 b, and the segment 810 c attaches to the pulmonary veincannulation interface 166. Using the bypass conduit 810 soattached/cannulated into the organ chamber assembly 104, an operator cancause the system 100 to circulate the perfusion fluid 108 through all ofthe paths used during actual operation. This enables the system 100 tobe thoroughly tested and primed prior to cannulating the heart 102 intoplace.

In the next step 912, blood from the donor is filtered and added to thereservoir 160. The filtering process helps reduce the inflammatoryprocess through the complete or partial removal of leukocytes andplatelets. Additionally, the donor blood is mixed with one or morenutritional 116 and/or preservative 118 solutions to form the perfusionfluid 108. In step 926, the system 100 is primed with the perfusionfluid 108 by pumping it through the system 100 in the retrograde flowmode, as described above in reference to FIG. 24B, and with the bypassconduit 810 in place. As the perfusion fluid 108 circulates through thesystem 100 in priming step 926, it is warmed to the desired temperatureas it passes through heater assembly 110. The desired temperature rangeand heating applications are described above in reference to FIGS. 6Athrough 6E, and in respect to FIG. 13 . In step 920, after the system100 is primed with the perfusion fluid 108, the bypass conduit 810 isremoved, and the heart 102 is instrumented, as described above and shownin FIG. 27B, onto the system 100.

After the heart 102 is instrumented onto the system 100, the pump 104 isactivated and the flow mode valve 112 is positioned in retrograde flowmode (described above with reference to FIGS. 1 and 4 ) to pump theperfusion fluid 108 in retrograde flow mode through the aorta into thevasculature of the heart 102. The pumping of the warm, oxygen andnutrient enriched perfusion fluid 108 through the heart 102 allows theheart 102 to function ex vivo in a near normal physiologic state. Inparticular, the warm perfusion fluid 108 warms the heart 102 as itperfuses through it, which may cause the heart 102 to resume beating inits natural fashion. In some instances, it is desirable to assist theheart 102 in resuming its beating, which may be done by providing handmassage or a defibrillation signal 143 (shown in FIG. 22E) to the heart102. This may be done as described above with reference to the organchamber assembly of FIGS. 5A-5F and operator interface 146 of FIGS.17A-17J.

After the heart is instrumented onto the system 100 at step 920,subsequent steps 928 and 930 allow the operator to test the heart 102and the system 100, and to evaluate their respective conditions.Illustratively, step 928 involves evaluating ECG signals 379 and 381from the sensors 142 and 144 (positioned as shown in FIG. 27A),respectively, as well as hematocrit 145 and oxygen saturation 141 levelsof the perfusion fluid 108 from the sensor 140. As further described inreference to FIG. 12 and FIGS. 17A-17I, the operator can also monitorthe fluid flows, pressures, and temperatures of the system 100 while theheart 102 is cannulated. As described above with reference to FIGS. 5Eand 5F, the testing step 928 may also include having the operatortouch/examine the heart 102 by lifting an outer lid 196 of the organchamber 104 and touching/examining the heart 102 indirectly through theflexible membrane 198 b. During the evaluation step 930, based on thedata and other information obtained during testing 928, the operatordetermines whether and how to adjust the system 100 properties (e.g.,fluid flows, pressures, and temperatures), and whether to provideadditional defibrillation, or other needed modes of treatment to theheart 102. The operator makes any such adjustments in step 932, thenrepeats steps 928 and 930 to re-test and re-evaluate the heart 102 andthe system 100. In certain embodiments, the operator may also opt toperform surgical, therapeutic or other procedures on the heart 102during the adjustment step 932. For example, the operator can conduct anevaluation of the physiological fitness of the heart, such as forexample, performing an ultrasound or other imaging test, performing anechocardiogram or diagnostic test on the heart, measuring arterial bloodgas levels and other evaluative tests.

In another application, during or after step 932, the system 100 allowsa medical operator to evaluate the organ for compatibility with anintended recipient after explantation but prior to implantation into thedonor. For example, the operator can perform a Human Leukocyte Antigen(HLA) matching test on the organ while the organ is cannulated to thesystem 100. Such tests may require 12 hours or longer and are performedto ensure compatibility of the organ with the intended recipient. Thepreservation of an organ using the system 100 described above may allowfor preservation times in excess of the time needed to complete an HLAmatch, potentially resulting in improved post-transplant outcomes. Inthe HLA matching test example, the HLA test can be performed on theheart while a preservation solution is pumping into the heart.

According to a further illustrative embodiment, after the heart isfunctioning as determined by the step 932, the operator can performsurgery on the heart or provide therapeutic or other treatment, such asimmunosuppressive treatments, chemotherapy, genetic testing andtherapies, or irradiation therapy. Because the system 100 allows theheart 102 to be perfused under near physiological temperature, fluidflow rate, and oxygen saturation levels, the heart 102 can be maintainedafter the adjustment step 932 for a long period of time (e.g., for aperiod of at least 3 days or more, greater than at least 1 week, atleast 3 weeks, or a month or more) to allow for repeated evaluation andtreatment.

According to the illustrative embodiment, the testing 928, evaluation930 and adjustment 932 steps may be conducted with the system 100operating in retrograde flow mode, or may be conducted with the system100 operating in normal flow mode. In normal flow mode, the operator cantest the function of the heart 102 under normal or near normalphysiologic blood flow conditions. Based on the evaluation 930, thesettings of the system 100 may be adjusted in step 932, if necessary, tomodify the flow, heating and/or other characteristics to stabilize theheart 102 in step 934 in preparation for transport to the recipient sitein step 936. After the heart 102 and the system 100 is tested andevaluated to ensure appropriate performance, the system 100 with theloaded heart 102 is transported to the recipient site at step 936.

Referring now to FIG. 30 , the first phase 942 of the transplant processinvolves repeating the testing 928 and evaluation 930 steps undertakenjust prior to leaving the donor site 936. If the function andcharacteristics of the heart 102 are not acceptable, the system 100 canbe adjusted 942 as appropriate, for example, to provide appropriatefluid oxygenation or nutritional levels, or to increase or decrease theappropriate fluid temperature. As noted above, surgical and/or othertherapeutic/remedial procedures may be performed on the heart 102, alongwith the testing 928 and evaluation 930. According to the illustrativeembodiment, testing at the recipient site may be performed in retrogradeflow mode, normal flow mode, or a combination of both.

At step 946, after testing is complete, the system 100 is placed innormal/forward flow mode. In certain embodiments, this step 946 is notinitiated until the left atrium 152 and pulmonary vein 164 arecannulated, there is adequate operating volume in the system, the heartexhibits stable electrical activity, the ABG and electrolytes are withinacceptable ranges, SvO2 is >80%, and blood temperature is between about34.degree. C. and about 36.degree. C. The step 946 is may beaccomplished by slowing and/or stopping the retrograde pumping of thesystem 100, then restarting the pumping in forward mode. In certainembodiments, prior to restarting in forward mode, the user opens theaortic sampling port 754 a, releases the pressure control clamp 190 byturning it counterclockwise, then increases the flow rate of pump 106 toabout 1.0 L/min, sets the flow control valve 112 to normal/forward flow,and increases the flow rate of pump 106 to about 2.0 L/min to allow theblood 102 to displace air in the perfusate lines (e.g., 802) of thesystem 100 and pass through the left side of the heart 102 and down thereservoir return line 808. The user then closes the aortic sampling port754 a.

The flow rate of the perfusion fluid 108 emitted from the pump 106 isthen increased at step 950 to a level of the clinician's choosing(typically between about 1 L/min to about 5 L/min) to approximate thephysiologic flow rate provided by the heart 102 while functioning innormal beating mode. The heart 102 and the system 100 are again testedat step 952 in a similar fashion to that described above with respect tosteps 928 and 930. The clinician may also choose to perform any othertests or evaluations on the heart, for example echocardiogram,electrolyte measurements, cardiac enzyme measurements, metabolytemeasurements, intravascular ultrasound evaluation, pressure-volume loopevaluation, and Millar pressure evaluation.

In the third phase 946 at the recipient site, the heart 102 is preparedfor implantation into the recipient. This phase includes the step 956 ofpowering down the pump 106 to stop the flow of perfusion fluid 108.Next, in step 958, the heart 102 is arrested, for example by injectingit with cardioplegic solution in a similar fashion to what is done instep 914 at the donor site. In step 960, the heart 102 is de-cannulatedand removed from the organ chamber assembly 106. In step 962, the heart102 is transplanted into the recipient patient by first removing thesutures 901 a-901 f, then inserting the heart 102 into the recipient'schest cavity, and suturing the various heart vesicles (e.g., 158, 164 a,164 b, 168 a, 168 b, 169 a, 169 b, and 903 a-903 f) to their appropriatemating vesicles within the recipient.

While external devices and methods have been described to defibrillatethe heart, deliver pacing signals to the heart, and perform bloodchemistry analyses from samples taken from the perfusion fluid, it mayalso be beneficial to integrate these features into the portable system.Such features include defibrillation, pacing, diagnostic ECG sensing,and blood chemistry analyses.

As described above, the system 100 employs a priming solution, and alsoemploys a perfusion fluid 108 that combines a nutritional supplement 116solution and a preservative solution 118 with a blood product orsynthetic blood product to form the perfusion fluid 108. The priming,supplement 116, and preservative 118 solutions are described next.

According to certain embodiments, solutions with particular solutes andconcentrations are selected and proportioned to enable the organ tofunction at physiologic or near physiologic conditions. For example,such conditions include maintaining organ function at or near aphysiological temperature and/or preserving an organ in a state thatpermits normal cellular metabolism, such as protein synthesis.

In certain embodiments solutions are formed from compositions bycombining components with a fluid, from more concentrated solutions bydilution, or from more dilute solutions by concentration. In exemplaryembodiments, suitable solutions include an energy source, one or morestimulants to assist the organ in continuing its normal physiologicfunction prior to and during transplantation, and one or more aminoacids selected and proportioned so that the organ continues its cellularmetabolism during perfusion. Cellular metabolism includes, for exampleconducting protein synthesis while functioning during perfusion. Someillustrative solutions are aqueous based, while other illustrativesolutions are non-aqueous, for example organic solvent-based,ionic-liquid-based, or fatty-acid-based.

The solutions may include one or more energy-rich components to assistthe organ in conducting its normal physiologic function. Thesecomponents may include energy rich materials that are metabolizable,and/or components of such materials that an organ can use to synthesizeenergy sources during perfusion. Exemplary sources of energy-richmolecules include, for example, one or more carbohydrates. Examples ofcarbohydrates include monosaccharides, disaccharides, oligosaccharides,polysaccharides, or combinations thereof, or precursors or metabolitesthereof. While not meant to be limiting, examples of monosaccharidessuitable for the solutions include octoses; heptoses; hexoses, such asfructose, allose, altrose, glucose, mannose, gulose, idose, galactose,and talose; pentoses such as ribose, arabinose, xylose, and lyxose;tetroses such as erythrose and threose; and trioses such asglyceraldehyde. While not meant to be limiting, examples ofdisaccharides suitable for the solutions include (+)-maltose(4-O-(.alpha.-D-glucopyranosyl)-.alpha.-D-glucopyranose), (+)-cellobiose(4-O-(.beta.-D-glucopyranosyl)-D-glucopyranose), (+)-lactose(4-O-(.beta.-D-galactopyranosyl)-.beta.-D-glucopyranose), sucrose(2-O-(.alpha.-D-glucopyranosyl)-.beta.-D-fructofuranoside). While notmeant to be limiting, examples of polysaccharides suitable for thesolutions include cellulose, starch, amylose, amylopectin,sulfomucopolysaccharides (such as dermatane sulfate, chondroitinsulfate, sulodexide, mesoglycans, heparan sulfates, idosanes, heparinsand heparinoids), and glycogen. In some embodiments, monossacharides,disaccharides, and polysaccharides of both aldoses, ketoses, or acombination thereof are used. One or more isomers, includingenantiomers, diastereomers, and/or tautomers of monossacharides,disaccharides, and/or polysaccharides, including those described and notdescribed herein, may be employed in the solutions described herein. Insome embodiments, one or more monossacharides, disaccharides, and/orpolysaccharides may have been chemically modified, for example, byderivatization and/or protection (with protecting groups) of one or morefunctional groups. In certain embodiments, carbohydrates, such asdextrose or other forms of glucose are preferred.

Other possible energy sources include adenosine triphosphate (ATP),co-enzyme A, pyruvate, flavin adenine dinucleotide (FAD), thiaminepyrophosphate chloride (co-carboxylase), .beta.-nicotinamide adeninedinucleotide (NAD), .beta.-nicotinamide adenine dinucleotide phosphate(NADPH), and phosphate derivatives of nucleosides, i.e. nucleotides,including mono-, di-, and tri-phosphates (e.g., UTP, GTP, GDF, and UDP),coenzymes, or other bio-molecules having similar cellular metabolicfunctions, and/or metabolites or precursors thereof. For example,phosphate derivatives of adenosine, guanosine, thymidine (5-Me-uridine),cytidine, and uridine, as well as other naturally and chemicallymodified nucleosides are contemplated.

In certain embodiments, one or more carbohydrates is provided along witha phosphate source, such as a nucleotide. The carbohydrate helps enablethe organ to produce ATP or other energy sources during perfusion. Thephosphate source may be provided directly through ATP, ADP, AMP or othersources. In other illustrative embodiments, a phosphate is providedthrough a phosphate salt, such as glycerophosphate, sodium phosphate orother phosphate ions. A phosphate may include any form thereof in anyionic state, including protonated forms and forms with one or morecounter ions.

The solutions may include one or more organ stimulants for assisting theorgan's normal physiologic function during perfusion. In someillustrative embodiments, where the transplanted organ is a heart,cardio stimulants are provided to enable the heart to continuefunctioning (e.g., continue beating) during perfusion andtransplantation. Such stimulants may include, for example,catecholamines, such as epinephrine and/or norepinephrine, whichfacilitate beating of the heart. Other cardio stimulants may be used,such as certain forms of peptides and/or polypeptides (e.g.,vasopressin, Anthropleurin-A and Anthropleurin-B), and/or.beta.1/.beta.2-adrenoreceptor blocking agents (such as CGP 12177),buplinarol, pindolol, alprenolol, and cardiac glycosides. One or morenatural products may also be used, such as digitalis (digoxin),palustrin, and/or ferulic acid. Stimulants such as those mentioned abovecan be included with the solutions or added at the point of use by theuser.

In some instances, additional components are provided to assist theorgan in conducting its metabolism during perfusion. These componentsinclude, for example, forms or derivatives of adenine and/or adenosine,which may be used for ATP synthesis, for maintaining endothelialfunction, and/or for attenuating ischemia and/or reperfusion injury.According to certain implementations, a magnesium ion source is providedwith a phosphate, and in certain embodiments, with adenosine to furtherenhance ATP synthesis within the cells of the perfused organ.

Solutions described herein may include one or more amino acids,preferably a plurality of amino acids, to support protein synthesis bythe organ's cells. Suitable amino acids include, for example, any of thenaturally-occurring amino acids. The amino acids may be, in variousenantiomeric or diastereomeric forms. For example, solutions may employeither D- or L-amino acids, or a combination thereof, i.e. solutionsenantioenriched in more of the D- or L-isomer or racemic solutions.Suitable amino acids may also be non-naturally occurring or modifiedamino acids, such as citrulline, ornithine, homocystein, homoserine,.beta.-amino acids such as .beta.-alanine, amino-caproic acid, orcombinations thereof

Certain exemplary solutions include some but not all naturally-occurringamino acids. In some embodiments, solutions include essential aminoacids. For example, a solution may be prepared with one or more or allof the following amino-acids:

-   -   Glycine    -   Alanine    -   Arginine    -   Aspartic Acid    -   Glutamic Acid    -   Histidine    -   Isoleucine    -   Leucine    -   Methionine    -   Phenylalanine    -   Proline    -   Serine    -   Thereonine    -   Tryptophan    -   Tyrosine    -   Valine    -   Lysine acetate

In certain embodiments, non-essential and/or semi-essential amino acidsare not included in the solutions. For example, in some embodiments,asparagine, glutamine, and/or cysteine are not included. In otherembodiments, the solution contains one or more non-essential and/orsemi-essential amino acids. Accordingly, in other embodiments,asparagine, glutamine, and/or cysteine are included.

The solutions may also contain electrolytes, particularly calcium ionsfor facilitating enzymatic reactions, cardiac contractility, and/orcoagulation within the organ. Other electrolytes may be used, such assodium, potassium, chloride, sulfate, magnesium and other inorganic andorganic charged species, or combinations thereof. It should be notedthat any component provided hereunder may be provided, where valence andstability permit, in an ionic form, in a protonated or unprotonatedform, in salt or free base form, or as ionic or covalent substituents incombination with other components that hydrolyze and make the componentavailable in aqueous solutions, as suitable and appropriate.

In certain embodiments, the solutions contain buffering components. Forexample, suitable buffer systems include 2-morpholinoethanesulfonic acidmonohydrate (IVIES), cacodylic acid, H.sub.2CO.sub.3/NaHCO.sub.3(pK.sub.a1), citric acid (pK.sub.a3),bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane (Bis-Tris),N-carbamoylmethylimidino acetic acid (ADA),3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris Propane)(pK.sub.a1), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES),N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), imidazole,N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES),3-(N-morpholino)propanesulphonic acid (MOPS),NaH.sub.2PO.sub.4Na.sub.2HPO.sub.4 (pK.sub.a2),N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES),N-(2-hydroxyethyl)-piperazine-N′-2-ethanesulfonic acid (HEPES),N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid)(HEPPSO), triethanolamine, N-[tris(hydroxymethyl)methyl]glycine(Tricine), tris hydroxymethylaminoethane (Tris), glycineamide,N,N-bis(2-hydroxyethyl) glycine (Bicine), glycylglycine (pK.sub.a2),N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or acombination thereof. In some embodiments, the solutions contain sodiumbicarbonate, potassium phosphate, or TRIS buffer.

The solutions may include other components to help maintain the organand protect it against ischemia, reperfusion injury and other illeffects during perfusion. In certain exemplary embodiments thesecomponents may include hormones (e.g., insulin), vitamins (e.g., anadult multi-vitamin, such as multi-vitamin MVI-Adult), and/or steroids(e.g., dexamethasone and SoluMedrol).

In another aspect, a blood product is provided with the solution tosupport the organ during metabolism. Exemplary suitable blood productsmay include whole blood, and/or one or more components thereof such asblood serum, plasma, albumin, and red blood cells. In embodiments wherewhole blood is used, the blood may be passed through a leukocyte andplatelet depleting filter to reduce pyrogens, antibodies and/or otheritems that may cause inflammation in the organ. Thus, in someembodiments, the solution employs whole blood that has been at leastpartially depleted of leukocytes and/or whole blood that has been atleast partially depleted of platelets.

The solutions are preferably provided at a physiological temperature andmaintained thereabout throughout perfusion and recirculation. As usedherein, “physiological temperature” is referred to as temperaturesbetween about 25.degree. C. and about 37.degree. C., for example,between about 30.degree. C. and about 37.degree. C., such as betweenabout 34.degree. C. and about 37.degree. C.

Table 1 sets forth components that are used in an exemplary aqueouspriming solution. The component amounts in Table 1 are relative to eachother and to the amount of aqueous solvent employed in the solution(about 500 mL in the exemplary embodiment) and may be scaled asappropriate. In certain embodiments, the quantity of aqueous solventvaries ± about 10%.

TABLE 1 Composition of Exemplary Priming Solution (about 500 mL aqueoussolution) Component Amount Specification Mannitol 12.5 g. ±about 10%Sodium Chloride 4.8 g. ±about 10% Potassium Chloride 185 mg. ±about 10%Magnesium Sulfate 185 mg. ±about 10% heptahydrate Sodium 900 mg. ±about10%. Glycerophosphate

The exemplary priming solution is added to the system 100 throughpriming step 924, as more fully described with reference to FIG. 29A.

With regard to the nutritional supplement solution 116, in certainembodiments it includes one or more carbohydrates and may also include aphosphate source. The nutritional supplement solution 116 is typicallymaintained at a pH of about 5.0 to about 6.5, for example about 5.5 toabout 6.0.

Table 2 sets forth components that are used in an exemplary nutritionalsupplement solution 116. In some embodiments, the nutritional solution116 further includes sodium glycerol phosphate. The amount of componentsin Table 2 is relative to the amount of aqueous solvent employed in thesolution 116 (about 500 mL) and may be scaled as appropriate. In someembodiments, the quantity of aqueous solvent varies ± about 10%.

TABLE 2 Components of Exemplary Nutritional Solution (about 500 mL)Component Amount Specification Dextrose 40 g. ±about 10%.

In certain embodiments the nutritional solution 116 includes one or morecarbohydrates and may also include a phosphate source. The nutritionalsolution 116 is typically maintained at a pH of about 5.0 to about 6.5,for example of about 5.5 to about 6.0.

The preservation solution 118 may include one or more preservatives. Inan exemplary embodiment, one or more cardio stimulants are included forassisting normal physiologic function of the heart 102 during perfusionand transplantation. Such stimulants may include, for example,catecholamines, such as epinephrine and/or norepinephrine, whichfacilitate beating of the heart.

Other components may be added to the preservation solution 118,including, for example, adenosine, magnesium, phosphate, calcium, and/orsources thereof. In some instances, additional components are providedto assist the organ in conducting its metabolism during perfusion. Thesecomponents include, for example, forms of adenosine, which may be usedfor ATP synthesis, for maintaining endothelial function, and/or forattenuating ischemia and/or reperfusion injury. Components may alsoinclude other nucleosides, such as guanosine, thymidine (5-Me-uridine),cytidine, and uridine, as well as other naturally and chemicallymodified nucleosides including nucleotides thereof. According to someimplementations, a magnesium ion source is provided with a phosphatesource, and in certain embodiments, with adenosine to further enhanceATP synthesis within the cells of the perfused organ. A plurality ofamino acids may also be added to support protein synthesis by theheart's 102 cells. Applicable amino acids may include, for example, anyof the naturally-occurring amino acids, as well as those mentionedabove.

Table 3 sets forth components that may be used in a solution 118 forpreserving an organ as described herein. The solution 118 may includeone or more of the components described in Table 3.

TABLE 3 Component of Exemplary Composition for Preservative SolutionExemplary Concentration Ranges in Component Preservative SolutionAlanine about 1 mg/L-about 10 g/L Arginine about 1 mg/L-about 10 g/LAsparagine about 1 mg/L-about 10 g/L Aspartic Acid about 1 mg/L-about 10g/L Cysteine about 1 mg/L-about 10 g/L Cystine about 1 mg/L-about 10 g/LGlutamic Acid about 1 mg/L-about 10 g/L Glutamine about 1 mg/L-about 10g/L Glycine about 1 mg/L-about 10 g/L Histidine about 1 mg/L-about 10g/L Hydroxyproline about 1 mg/L-about 10 g/L Isoleucine about 1mg/L-about 10 g/L Leucine about 1 mg/L-about 10 g/L Lysine about 1mg/L-about 10 g/L Methionine about 1 mg/L-about 10 g/L Phenylalanineabout 1 mg/L-about 10 g/L Proline about 1 mg/L-about 10 g/L Serine about1 mg/L-about 10 g/L Threonine about 1 mg/L-about 10 g/L Tryptophan about1 mg/L-about 10 g/L Tyrosine about 1 mg/L-about 10 g/L Valine about 1mg/L-about 10 g/L Adenine about 1 mg/L-about 10 g/L ATP about 10ug/L-about 100 g/L Adenylic Acid about 10 ug/L-about 100 g/L ADP about10 ug/L-about 100 g/L AMP about 10 ug/L-about 100 g/L Ascorbic Acidabout 1 ug/L-about 10 g/L D-Biotin about 1 ug/L-about 10 g/L VitaminD-12 about 1 ug/L-about 10 g/L Cholesterol about 1 ug/L-about 10 g/LDextrose (Glucose) about 1 g/L-about 150 g/L Multi-vitamin Adult about 1mg/L-about 20 mg/L or 1 unit vial Epinephrine about 1 ug/L-about 1 g/LFolic Acid about 1 ug/L-about 10 g/L Glutathione about 1 ug/L-about 10g/L Guanine about 1 ug/L-about 10 g/L Inositol about 1 g/L-about 100 g/LRiboflavin about 1 ug/L-about 10 g/L Ribose about 1 ug/L-about 10 g/LThiamine about 1 mg/L-about 10 g/L Uracil about 1 mg/L-about 10 g/LCalcium Chloride about 1 mg/L-about 100 g/L NaHCO₃ about 1 mg/L-about100 g/L Magnesium sulfate about 1 mg/L-about 100 g/L Potassium chlorideabout 1 mg/L-about 100 g/L Sodium about 1 mg/L-about 100 g/Lglycerophosphate Sodium Chloride about 1 mg/L-about 100 g/L SodiumPhosphate about 1 mg/L-about 100 g/L Insulin about 1 IU-about 150 IUSerum albumin about 1 g/L-about 100 g/L Pyruvate about 1 mg/L-about 100g/L Coenzyme A about 1 ug/L-about 10 g/L Serum about 1 ml/L-about 100ml/L Heparin about 500 U/L-about 1500 U/L Solumedrol about 200mg/L-about 500 mg/L Dexamethasone about 1 mg/L-about 1 g/L FAD about 1ug/L-about 10 g/L NADP about 1 ug/L-about 10 g/L adenosine about 1mg/L-about 10 g/L guanosine about 1 mg/L-about 10 g/L GTP about 10ug/L-about 100 g/L GDP about 10 ug/L-about 100 g/L GMP about 10ug/L-about 100 g/L

Table 4 sets forth components that are used in an exemplary preservativesolution 118. The amounts provided in Table 4 describe preferred amountsrelative to other components in the table and may be scaled to providecompositions of sufficient quantity. In some embodiments, the amountslisted in Table 4 can vary by ± about 10% and still be used in thesolutions described herein.

TABLE 4 Components of Exemplary Preservative Solution Component AmountAdenosine About 675 mg-About 825 mg Calcium Chloride dihydrate About2100 mg-About 2600 mg Glycine About 315 mg-About 385 mg L-Alanine About150 mg-About 200 mg L-Arginine About 600 mg-About 800 mg L-Aspartic AcidAbout 220 mg-About 270 mg L-Glutamic Acid About 230 mg-About 290 mgL-Histidine About 200 mg-About 250 mg L-Isoleucine About 100 mg about130 mg L-Leucine About 300 mg-About 380 mg L-Methionine About 50mg-About 65 mg L-Phenylalanine About 45 mg-About 60 mg L-Proline About110 mg-About 140 mg L-Serine About 80 mg-About 105 mg L-Thereonine About60 mg-About 80 mg L-Tryptophan About 30 mg-About 40 mg L-Tyrosine About80 mg-About 110 mg L-Valine About 150 mg-About 190 mg Lysine AcetateAbout 200 mg-About 250 mg Magnesium Sulfate About 350 mg-About 450 mgHeptahydrate Potassium Chloride About 15 mg-About 25 mg Sodium ChlorideAbout 1500 mg-About 2000 mg Dextrose About 25 gm-About 120 gmEpinephrine About 0.25 mg-About 1.0 mg Insulin About 75 Units-About 150Units MVI-Adult 1 unit vial SoluMedrol About 200 mg-500 mg SodiumBicarbonate About 10-25 mEq

In the exemplary embodiment of a solution 118, the components in Table 4are combined in the relative amounts listed therein per about 1 L ofaqueous fluid to form the solution 118. In some embodiments, thecomponents in Table 4 are combined in the relative amounts listedtherein per about 500 mL of aqueous fluid and then combined with thesolution 116, also about 500 mL, to provide a maintenance solution116/118 of about 1 L of aqueous fluid. In some embodiments the quantityof aqueous fluid in solutions 116, 118, and/or 116/118 can vary ± about10%. The pH of the solution 118 may be adjusted to be between about 7.0and about 8.0, for example about 7.3 and about 7.6. The solution 118 maybe sterilized, for example by autoclaving, to provide for improvedpurity.

Table 5 sets forth another exemplary preservative solution 118,comprising a tissue culture media having the components identified inTable 5 and combined with an aqueous fluid, which may be used in theperfusion fluid 108 as described herein. The amounts of componentslisted in Table 5 are relative to each other and to the quantity ofaqueous solution used. In some embodiments, about 500 mL of aqueousfluid is used. In other embodiments about 1 L of aqueous fluid is used.For example, combination of about 500 mL of preservative solution 118with 500 mL of nutritional solution 116 affords a maintenance solution116/118 of about 1 L. In some embodiments, the quantity of aqueoussolution can vary ± about 10%. The component amounts and the quantity ofaqueous solution may be scaled as appropriate for use. The pH of thepreservative solution 118, in this embodiment, may be adjusted to beabout 7.0 to about 8.0, for example about 7.3 to about 7.6.

TABLE 5 Composition of Another Exemplary Preservative Solution (about500 mL aqueous solution) Tissue Culture Component Amount SpecificationAdenosine 750 mg. ±about 10% Calcium Chloride dihydrate 2400 mg ±about10% Glycine 350 mg ±about 10% L-Alanine 174 mg ±about 10% L-Arginine 700mg ±about 10% L-Aspartic Acid 245 mg ±about 10% L-Glutamic Acid 258 mg±about 10% L-Histidine 225 mg ±about 10% L-Isoleucine 115.5 mg ±about10% L-Leucine 343 mg ±about 10% L-Methionine 59 mg ±about 10%L-Phenylalanine 52 mg ±about 10% L-Proline 126 mg ±about 10% L-Serine 93mg ±about 10% L-Thereonine 70 mg ±about 10% L-Tryptophan 35 mg ±about10% L-Tyrosine 92 mg ±about 10% L-Valine 171.5 mg ±about 10% LysineAcetate 225 mg ±about 10% Magnesium Sulfate 400 mg ±about 10%Heptahydrate Potassium Chloride 20 mg ±about 10% Sodium Chloride 1750 mg±about 10%

Since amino acids are the building blocks of proteins, the uniquecharacteristics of each amino acid impart certain important propertieson a protein such as the ability to provide structure and to catalyzebiochemical reactions. The selection and concentrations of the aminoacids provided in the preservative solutions provide support of normalphysiologic functions such as metabolism of sugars to provide energy,regulation of protein metabolism, transport of minerals, synthesis ofnucleic acids (DNA and RNA), regulation of blood sugar and support ofelectrical activity, in addition to providing protein structure.Additionally, the concentrations of specific amino acids found in thepreservative solutions can be used to predictably stabilize the pH ofthe maintenance solution 116/118 and perfusion fluid 108.

Certain embodiments of the preservative solution 118 include epinephrineand a plurality of amino acids. In certain embodiments, the preservativesolution 118 includes electrolytes, such as calcium and magnesium.

In one embodiment, a maintenance solution 116/118 is made from thecombination of the preservative solution 118, including one or moreamino acids, and the nutritional solution 116, including one or morecarbohydrates, such as glucose or dextrose. The maintenance solution116/118 may also have additives, such as those described herein,administered at the point of use just prior to infusion into the organperfusion system. For example, additional additives that can be includedwith the solution or added at the point of use by the user includehormones and steroids, such as dexamethasone and insulin, as well asvitamins, such as an adult multi-vitamin, for example adultmultivitamins for infusion, such as MVI-Adult. Additional smallmolecules and large bio-molecules may also be included with the solutionor added at the point of use by the user at port 762, for example,therapeutics and/or components typically associated with blood or bloodplasma, such as albumin.

In some embodiments, therapeutics that may be included in thecompositions, solutions, and systems described herein include hormones,such as thyroid hormones, for example T.sub.3 and/or T.sub.4 thyroidhormones. Further therapeutics that may be included include drugs suchas anti-arrhythmic drugs, for example, for heart therapy, and betablockers. For instance, in certain embodiments, one or more thyroidhormones, one or more anti-arrhythmic drugs, and one or more betablockers are added to the nutritional solution 116, the preservativesolution 118, and/or the maintenance solutions 116/118 either before orduring perfusion of the organ. The above therapeutics may also be addeddirectly to the system, for example, to the perfusion fluid 108, beforeor during perfusion of the organ.

With further reference to Table 4, certain components used in theexemplary preservation solution 118 are molecules, such as small organicmolecules or large bio-molecules, that would be inactivated, for examplethrough decomposition or denaturing, if passed through sterilization.According to the system 100, the inactivatable components of thesolution 118 may be prepared separately from the remaining components ofthe solution 118. The separate preparation involves separately purifyingeach component through known techniques. The remaining components of thesolution 118 are sterilized, for example through an autoclave, thencombined with the biological components.

Table 6 lists certain biological components that may be separatelypurified and added to the solutions described herein aftersterilization, according to this two-step process. These additional orsupplemental components may be added to solutions 118, 116, 116/118, thepriming solution or a combination thereof individually, in variouscombinations, all at once as a composition, or as a combined solution.For example, in certain embodiments, the epinephrine, insulin, andMVI-Adult, listed in Table 6, are added to the maintenance solution116/118. In another example, the SoluMedrol and the sodium bicarbonate,listed in Table 6, are added to the priming solution. The additionalcomponents may also be combined in one or more combinations or alltogether and placed in solution before being added to solutions 116,118, 116/118, and/or the priming solution. In some embodiments, theadditional components are added directly to the perfusion fluid 108through port 762. The component amounts listed in Table 6 are relativeto each other and/or to the amounts of components listed in one or moreof Tables 1-5 as well as the amount of aqueous solution used inpreparing solutions 116, 118, 116/118, and/or the priming solution andmay be scaled as appropriate for the amount of solution required.

TABLE 6 Exemplary Biological Components Added Prior to Use ComponentAmount Type Specification Epinephrine About 0.50 mg Catecholamine ±about10% Hormone Insulin about 100 Units Hormone ±about 10% MVI-Adult 1 mLunit vial Vitamin ±about 10% SoluMedrol About 250 mg Steroid ±about 10%Sodium About 20 mEq Buffer ±about 10% Bicarbonate

In one embodiment, a composition for use in a maintenance solution116/118 is provided comprising one or more carbohydrates, one or moreorgan stimulants, and a plurality of amino acids that do not includeasparagine, glutanine, or cysteine. The composition may also includeother substances, such as those used in solutions described herein.

In another embodiment, a system for perfusing an organ, such as a heart,is provided comprising an organ and a substantially cell-freecomposition, comprising one or more carbohydrates, one or more organstimulants, and a plurality of amino acids that do not includeasparagine, glutamine, or cysteine. Substantially cell-free includessystems that are substantially free from cellular matter; in particular,systems that are not derived from cells. For example, substantiallycell-free includes compositions and solutions prepared from non-cellularsources.

In another aspect, the solutions 116 and 118 may be provided in the formof a kit that includes one or more organ maintenance solutions. Anexemplary maintenance solution may include components identified abovein one or more fluid solutions for use in an organ perfusion fluid 108.In certain embodiments, the maintenance solution 116/118 may includemultiple solutions, such as a preservation solution 118 and anutritional solution 116 and/or a supplemental composition or solution,or may include dry components that may be regenerated in a fluid to formone or more solutions 116/118. The kit may also comprise components fromthe solutions 116 and/or 118 in one or more concentrated solutionswhich, on dilution, provide a preservation, nutritional, and/orsupplemental solution as described herein. The kit may also include apriming solution. In an exemplary embodiment, the maintenance solutionincludes a preservation solution 118 and a nutritional solution 116 suchas those described above, and a priming solution such as that describedabove.

In certain embodiments, the kit is provided in a single package, whereinthe kit includes one or more solutions (or components necessary toformulate the one or more solutions by mixing with an appropriatefluid), and instructions for sterilization, flow and temperature controlduring perfusion and use and other information necessary or appropriateto apply the kit to organ perfusion. In certain embodiments, a kit isprovided with only a single solution 116, 118 and/or 116/118 (or set ofdry components for use in a solution upon mixing with an appropriatefluid), and the single solution 116, 118 and/or 116/118 (or set of drycomponents) is provided along with a set of instructions and otherinformation or materials necessary or useful to operate the solution116, 118 and/or 116/118 in the system 100.

In another aspect, the systems, solutions and methods may be used todeliver therapeutics to an organ during perfusion. For example, one ormore of the solutions and/or systems described above may include one ormore drugs, biologics, gene therapy vectors, or other therapeutics whichare delivered to the organ during perfusion. Suitable exemplarytherapeutics may include drugs, biologics, or both. Suitable drugs mayinclude, for example, anti fungals, anti-microbials or anti-biotics,anti-inflamatories, anti-proliferatives, anti-virals, steroids,retinoids, NSAIDs, vitamin D3 and vitamin D3 analogs, calcium channelblockers, complement neutralizers, ACE inhibitors, immuno-suppressants,and other drugs. Suitable biologics may include proteins; suitablebiologics may also include vectors loaded with one or more genes forgene therapy application.

For example, suitable steroids include but are not limited to androgenicand estrogenic steroid hormones, androgen receptor antagonists and5-.alpha.-reductase inhibitors, and corticosteroids. Specific examplesinclude but are not limited to alclometasone, clobetasol, fluocinolone,fluocortolone, diflucortolone, fluticasone, halcinonide, mometasone,prednisone, prednisolone, methylprednisolone, triamcinolone,betamethasone, and dexamethasone, and various esters and acetonidesthereof.

Suitable retinoids include but are not limited to retinol, retinal,isotretinoin, acitretin, adapalene, tazarotene, and bexarotene.

Suitable NSAIDs include but are not limited to naproxen, suprofen,ketoprofen, ibuprofen, flurbiprofen, diclofenac, indomethacin,celecoxib, and rofecoxib.

Suitable vitamin D3 analogues include but are not limited todoxercalciferol, seocalcitol, calcipotriene, tacalcitol, calcitriol,ergocalciferol, and calcifediol.

Suitable anti-viral agents include but are not limited to trifluridine,cidofovir, acyclovir, penciclovir, famciclovir, valcyclovir,gancyclovir, and docosanol.

Suitable human carbonic anhydrase inhibitors include but are not limitedto methazoliamide, acetazolamide, and dorzolamide.

Suitable anti-proliferative agents include but are not limited to 5-FU,taxol, daunorubicin, and mitomycin.

Suitable antibiotic (antimicrobial) agents include but are not limitedto bacitracin, chlorhexidine, chlorhexidine digluconate, ciprofloxacin,clindamycin, erythromycin, gentamicin, lomefloxacin, metronidazole,minocycline, moxifloxacin, mupirocin, neomycin, ofloxacin, polymyxin B,rifampicin, ruflozacin, tetracycline, tobramycin, triclosan, andvancomycin. The antiviral and antibacterial prodrugs described hereinmay be used to treat appropriately responsive systemic infections.

In certain embodiments, a solution system for use in a perfusion fluid108, comprising a first chamber containing a first solution, such as apreservation solution 118, that includes one or more cardio stimulantsand a plurality of amino acids that do not include asparagine,glutamine, or cysteine, and a second chamber, containing a secondsolution, such as a nutritional solution 116, that includes one or morecarbohydrates, such as dextrose. The system may also include asterilization system for sterilizing the first solution and the secondsolution prior to using the solutions to perfuse a heart. In someembodiments, one or more of the solutions 118 and 116 includes one ormore therapeutics. In some embodiments the solution system includes athird chamber comprising a priming solution, such as is described above,which may have one or more carbohydrates. In certain embodiments, thefirst solution 118 includes epinephrine, adenosine, insulin, one or moreimmuno-suppressants, a multi-vitamin, and/or one or more electrolytes.

Certain experimental data are available to describe certain embodimentsof the solutions described herein and their use in organ perfusion.Certain data are set for in FIGS. 31-33 . FIG. 31 depicts a chartdemonstrating electrolyte stability for an organ under going perfusionin forward mode according to an embodiment of the system 100. In theembodiment associated with FIG. 31 , the organ is a heart 102 whereinperfusion is conducted in forward mode (as described above) by pumpingperfusion fluid 108 containing solution 116/118 to the let atria 152 andout of the aorta 158. The rate of perfusion is approximately 30 mhr. Ascan be seen from FIG. 31 , the levels of various electrolytes: sodium,potassium, calcium, and chloride ions, as well as dissolved glucose,remain at stable levels throughout the course of perfusion, from beforethe organ is cannulated to the perfusion system 100 to six hours aftercannulation within the system 100.

FIG. 32 depicts a chart demonstrating electrolyte stability for an organunder going retrograde perfusion according to another embodiment of thesystem 100. In the embodiment associated with FIG. 32 , the organ is aheart wherein perfusion occurs by pumping the perfusion fluid 108containing the solution 116/118 into the aorta 158 and through thecoronary sinus 155. The rate of perfusion is approximately 30 mL/hr. Ascan be seen from FIG. 32 , the levels of various electrolytes: sodium,potassium, calcium, and chloride ions, as well as dissolved glucose,remain at stable levels throughout the course of perfusion, from beforethe organ is cannulated to the perfusion system 100 to six hours aftercannulation. FIG. 32 also demonstrates that the levels of theelectrolytes and glucose remain at levels similar to those for the baseline (BL) normal physiological state for the organ.

FIG. 33 depicts a chart demonstrating the arterial blood gas profile foran organ under going perfusion according to another embodiment of theinvention. As can be seen from FIG. 33 , the levels of various bloodgasses: carbon dioxide and oxygen, and pH remain at stable levelsthroughout the six hour course of perfusion. FIG. 33 also demonstratesthat the levels of carbon dioxide, oxygen, and pH remain at levelssimilar to those for two base line (BL) measurements for the normalphysiological state for the organ. FIGS. 31-33 demonstrate the abilityof the present systems and methods to maintain an organ under stablephysiological or near physiological conditions.

In another aspect of the invention, lactate is used as an indicator ofisolated donor heart perfusion status. In Arterial blood lactate ismeasured using a standard blood chemistry analyzer or as a built inorgan care system 100 arterial on-line Lactate analyzer probe. Thevenous blood (which has been through the coronary sinus) lactate ismeasured using a similar technique as above. The V-A lactatedifferential is calculated using the following formula: Lactate V-Adifferential=Venous (coronary sinus) blood lactate−Arterial bloodlactate.

The V-A differential indicates the perfusion status.

If the V-A Differential has a negative (−) value the venous blood(coronary sinus), has less lactate than the arterial blood. Thisindicates that the heart is actually metabolizing lactate which is asign of adequate perfusion and oxygen delivery to the myocardial cells.

If the V-A Differential has a zero (0) value the lactate in the venousside is equal to the arterial blood. This indicates that the myocardialcells are not producing or metabolizing lactate. This state indicatesadequate perfusion for the myocardial cell, however, serial measurementsare needed to validate that this state of equilibrium is not shifting.

If the V-A Differential has a positive (+) value the myocardial cellsare starved of oxygen and are starting to produce lactate as a byproductof anaerobic metabolism. To address this issue, the operator wouldincrease the coronary flow to ensure adequate perfusion and increase therate of delivery of oxygen and substrate to the myocardial cells.

Serial (at least hourly) measurements of the lactate V-A differentialare indicated for the entire maintenance period of an isolated heart onthe organ care system 100 to give the operator a continuous assessmentof the perfusion status of that heart. The serial measurements allow theoperator to evaluate the trend data for the lactate V-A differential.

FIG. 34 depicts a serial lactate differential that indicates adequateperfusion. The vertical axis indicates the lactate value (mmol/L) andthe horizontal axis is time (minutes). The table below provides thevalues for aterial lactate (Lactate A), venous lactate (Lactate V) andLactate V-A differential (Lactate VA dif) and the time, in minutes, onthe perfusion clock.

TABLE 7 Serial lactate table of information corresponding to FIG. 34.Perfusion Lactate A Lactate VA Dif Lactate V Time 1.87 0 1.87 0 20 401.63 −0.24 1.39 60 80 100 1.01 −0.08 0.93 120 140 0.91 −0.08 0.83 160

Notable is that the V-A differential is zero or lower throughout theperfusion time. This indicates that there is adequate perfusion and thatthe myocardial cells are not producing lactate. In one embodiment,serial reading can provide the trend of the V-A differential. Further,the trend of decreasing lactate values indicates that the myocardialcells are metabolizing lactate. These indications are associated withpositive post transplant outcomes.

FIG. 35 is an example of serial lactate V-A differential assessment of ahuman heart on an organ care system 100. Notable is the increasinglactate values, indicating the myocardial cells are creating lactate andthe positive values for the VA differential. This indicates aninadequate perfusion and was associated with ischemic injury to thedonor heart resulting in a clinical decision of not being suitable fortransplantation. Further, the trend of increasing lactate valuesindicates the production of lactate and indicates that the myocardialcells lack sufficient oxygen.

TABLE 8 Serial lactate table of information corresponding to FIG. 35.Perfusion Lactate A Lactate VA Dif Lactate V Time 1.32 −0.06 1.26 101.45 0.11 1.56 30 4.54 0.11 4.65 150 4.81 180 8.1 −0.1 8 250 8.7 −0.58.2 280

The serial lactate differential can be used in combination with otherphysiologic parameters to assess the myocardial tissue suitability for atransplant. For example, Coronary Vascular Patency of an isolated hearton the Organ Care System 100 can be assessed using the combination ofhigh aortic pressure (perfusion pressure) and serial lactate V-ADifferential.

Particularly, the presence of elevated aortic pressure observed in aheart on the organ care system 100, combined with elevated, rising orneutral lactate V-A differential may indicate coronary vascularnarrowing of the perfused heart. This can be explained by the elevatedpressures as a sign of high resistance to blood flow and in turn low orinadequate oxygen delivery to the myocardial cells resulting in lactateproduction and the abnormal V-A differential.

It is to be understood that while the invention has been described inconjunction with the various illustrative embodiments, the forgoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Forexample, a variety of systems and/or methods may be implemented based onthe disclosure and still fall within the scope of the invention. Otheraspects, advantages, and modifications are within the scope of thefollowing claims. All references cited herein are incorporated byreference in their entirety and made part of this application.

What we claim is:
 1. A system comprising: an organ chamber assemblycomprising: a fluid conduit comprising: a first interface configured toconnect to an aorta of a heart; and a second interface configured toconnect to a pulmonary artery of the heart; a first sensor configured tomeasure a first lactate value in the first interface; and a secondsensor configured to measure a second lactate value in the secondinterface; and a processor configured to: calculate a lactatedifferential based on the first lactate value and the second lactatevalue; and correlate the lactate differential with a suitability of theheart for transplantation.
 2. The system of claim 1, wherein the organchamber assembly is disposable.
 3. The system of claim 1, wherein theprocessor is configured to: calculate the lactate differential at leastonce per hour.
 4. The system of claim 1, comprising a flow mode selectorvalve configured to: control a flow of a perfusion fluid to the firstinterface and to the second interface.
 5. The system of claim 1,comprising: a chassis; and a reservoir mounted to the chassis, thereservoir in fluid communication with the organ chamber assembly andconfigured to hold a perfusion fluid.
 6. The system of claim 1,comprising: a third sensor configured to measure an aortic pressure. 7.The system of claim 6, wherein the processor is configured to: receivean aortic pressure measurement from the third sensor; and evaluate acoronary vascular patency of the heart using the aortic pressuremeasurement and at least one of the first lactate value or the secondlactate value.
 8. The system of claim 1, wherein the processor isconfigured to: calculate the lactate differential at a periodicinterval.
 9. The system of claim 8, wherein the periodic interval isless than one hour.
 10. The system of claim 9, wherein the processor isconfigured to: receive, over a total length of time that is more thanone hour, the first lactate value and the second lactate value.
 11. Anapparatus comprising: a first fluid channel configured to be coupled toan aorta of a heart; a second fluid channel configured to be coupled toa pulmonary artery of the heart; a first sensor configured to measure afirst lactate level in the first fluid channel; a second sensorconfigured to measure a second lactate level in the second fluidchannel; a processor coupled to the first sensor and to the secondsensor; and a memory coupled to the processor and includingcomputer-readable instructions that, when executed by the processor,cause the processor to: calculate a lactate differential at twodifferent times using the first lactate level and the second lactatelevel.
 12. The apparatus of claim 11, wherein the first fluid channeland the second fluid channel are disposable.
 13. The apparatus of claim11, wherein the computer-readable instructions cause the processor to:calculate the lactate differential at least once per hour.
 14. Theapparatus of claim 11, comprising a flow mode selector valve configuredto: control a flow of a perfusion fluid through the first fluid channeland through the second fluid channel.
 15. The apparatus of claim 11,comprising: a chassis; and a reservoir mounted to the chassis, thereservoir in fluid communication with at least one of the first fluidchannel or the second fluid channel and configured to hold a perfusionfluid.
 16. The apparatus of claim 11, comprising: a third sensorconfigured to measure an aortic pressure.
 17. The apparatus of claim 16,wherein the computer-readable instructions cause the processor to:receive an aortic pressure measurement from the third sensor; andevaluate a coronary vascular patency of the heart using the aorticpressure measurement and at least one of the first lactate value or thesecond lactate value.
 18. The apparatus of claim 11, wherein thecomputer-readable instructions cause the processor to: calculate thelactate differential at a periodic interval.
 19. The apparatus of claim18, wherein the periodic interval is less than one hour.
 20. Theapparatus of claim 19, wherein the computer-readable instructions causethe processor to: receive, over a total length of time that is more thanone hour, the first lactate value and the second lactate value.
 21. Amethod comprising: placing an ex-vivo heart in an organ chamberassembly; connecting an aorta of the ex-vivo heart to a first interfaceof a fluid conduit; connecting a pulmonary artery of the ex-vivo heartto a second interface of the fluid conduit; measuring a first lactatevalue using a first sensor located in the first interface; measuring asecond lactate value using a second sensor located in the secondinterface; calculating a lactate differential based on the first lactatevalue and the second lactate value; and correlating the lactatedifferential with a suitability of the ex-vivo heart fortransplantation.
 22. The method of claim 21, comprising: calculating thelactate differential at least once per hour.
 23. The method of claim 21,comprising: measuring an aortic pressure using a third sensor.
 24. Themethod of claim 23, comprising: evaluating a coronary vascular patencyof the ex-vivo heart using the aortic pressure and at least one of thefirst lactate value or the second lactate value.
 25. The method of claim21, comprising: calculating the lactate differential at a periodicinterval.
 26. The method of claim 25, wherein the periodic interval isless than one hour.